CN101039904B - Heterocyclic compounds suitable for treating disorders that respond to modulation of the dopamine d3 receptor - Google Patents

Heterocyclic compounds suitable for treating disorders that respond to modulation of the dopamine d3 receptor Download PDF

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CN101039904B
CN101039904B CN200580035304.0A CN200580035304A CN101039904B CN 101039904 B CN101039904 B CN 101039904B CN 200580035304 A CN200580035304 A CN 200580035304A CN 101039904 B CN101039904 B CN 101039904B
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phenyl
fluoro
alkyl
methyl
ethyl
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CN101039904A (en
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K·德里舍
A·豪普特
L·昂格
S·C·特纳
W·布拉杰
R·格兰德尔
C·亨里
G·巴克菲什
A·贝耶巴克
W·鲁比施
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AbbVie Deutschland GmbH and Co KG
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

The invention relates to compounds of the formula (I) wherein n is 0, 1 or 2; G is CH2 or CHR3; R1 is H, C,-C6-alkyl, C,-C6-alkyl substituted by C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, fluorinated C,-C6-alkyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C3-C6 alkenyl, fluorinated C3-C6-alkenyl, formyl, acetyl or propionyl; R2, R3 and R4 are, independently of each other, H, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl; A is phenylene, pyridylene, pyrimidylene, pyrazinylene, pyridazinylene or thiophenylene, which can be substituted by one or more substituents selected from halogen, methyl, methoxy and CF3; E is NR5 or CH2, wherein R5 is H or C1-C3-alkyl; Ar is a cyclic radical selected from the group consisting of phenyl, a 5- or 6-membered heteroaromatic radical comprising as ring members 1, 2 or 3 heteroatoms selected from N, O and S and a phenyl ring fused to a saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic ring, where the heterocyclic ring comprises as ring members 1, 2 or 3 heteroatoms selected from N, O and S and/or 1, 2 or 3 heteroatom-containing groups each independently selected from NR8, where R8 is H, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4alkylcarbonyl or fluorinated C1-C4-alkylcarbonyl, and where the cyclic radical Ar may carry 1, 2 or 3 substituents Ra, wherein the variable Ra has the meanings given in the claims and in the description; and physiologically tolerated acid addition salts thereof.; The invention also relates to the use of a compound of the formula I or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the treatment of a medical disorder susceptible to treatment with a dopamine D3 receptor ligand.

Description

Be suitable for treatment for dopamine D 3the heterogeneous ring compound of the illness that regulation responds
Background of invention
The present invention relates to new heterogeneous ring compound.Described compound has valuable therapeutic property, and is applicable to particularly treat for dopamine D 3the disease that the adjusting of acceptor responds.
Neurone obtains its information by g protein coupled receptor particularly.Large quantity of material applies its effect by these acceptors.Wherein a kind of material is Dopamine HCL.There is Dopamine HCL and have the discovery confirming aspect the physiological function of neurotransmitter.Obstacle in dopaminergic mediator system causes central nervous system disease, comprises for example schizophrenia, dysthymia disorders and Parkinson's disease.These diseases and Other diseases are with treating with the interactional medicine of Dopamine Receptors.
Until nineteen ninety, two kinds of hypotypes, i.e. D of Dopamine Receptors aspect pharmacology, have clearly been defined 1and D 2acceptor.Recently, had been found that the third hypotype, i.e. D 3acceptor, it seems to mediate some effect (people such as J.C.Schwartz, the TheDopamine D of antipsychotics and anti-Parkinson medicine 3receptor as a Target for Antipsychotics, in NovelAntipsychotic Drugs, H.Y.Meltzer, Ed.Raven Press, New York1992, pages135-144; M.Dooley et al., Drugs and Aging1998,12,495-514, J.N.Joyce, Pharmacology and Therapeutics2001,90, pp.231-59 ＂ The Dopamine D 3receptor as a Therapeutic Target for Antipsychotic and AntiparkinsonianDrugs ＂).
Hereafter, Dopamine Receptors has been divided into Liang Ge family.On the one hand, be D 2group, by D 2, D 3and D 4acceptor forms, and on the other hand, is D 1group, by D 1and D 5acceptor forms.Yet, D 1and D 2acceptor is extensively to distribute, D 3seemingly regioselectivity expression of acceptor.Therefore, these acceptors are preferentially found in limbic system and half edge dopamine system, especially, in nucleus nervi acustici, still also in other region, for example in tonsilla, have also found.Since this comparison domain selective expression, D 3acceptor is regarded as having the target of few side effects, and has people to suppose, although selective d 3part will have the character of known antipsychotics, but it will not have their dopamine D 2receptor-mediated neurological side effects (the people Localization and Function of the D such as P.Sokoloff 3dopamine Receptor, arzneim Forsch./Drug Res.42(1), 224 (1992); The people .Molecular Cloning and Characterization of a Novel DopamineReceptor (D such as P.Sokoloff 3) as aTarget for Neuroleptics, nature, 347, 146 (1990)).
Prior art has been described for dopamine D in a lot of occasions 3acceptor has the compound of avidity, for example WO 95/04713, WO 96/23760, WO 97/45503, WO98/27081 and WO 99/58499.Some have medium avidity and/or selectivity for dopamine D 3 receptor certain in the middle of these compounds.Therefore they be suggested and be suitable for treating central nervous system disease.Some compound of describing in these publications has pyrrolidyl phenyl structure.Regrettably, they are towards D 3the avidity of acceptor and selectivity or their pharmacological property are unsatisfactory.Therefore, continuing to provide new compound, and these new compounds have the selectivity of high affinity and improvement.These compounds should also have good pharmacological characteristics, and for example high brain blood plasma ratio, high bioavailability, good metabolic stability or the mitochondrial respiratory of reduction suppress.
Summary of the invention
The present invention is based on high selectivity dopamine D is provided 3the object of the compound of receptors ligand effect.This object through type I compound and physiology thereof can tolerate acid salt and be achieved astoundingly
Wherein
N is 0,1 or 2;
G is CH 2or CHR 3;
R 1h, C 1-C 6-alkyl, by C 3-C 6the C of-cycloalkyl substituted 1-C 6-alkyl, C 1-C 6-hydroxyalkyl, fluoro C 1-C 6-alkyl, C 3-C 6-cycloalkyl, fluoro C 3-C 6-cycloalkyl, C 3-C 6-alkenyl, fluoro C 3-C 6-alkenyl, formyl radical, ethanoyl or propionyl;
R 2, R 3and R 4be H, methyl, methyl fluoride, difluoromethyl or trifluoromethyl independently of one another;
A is phenylene, pyridylidene, sub-pyrimidyl, sub-pyrazinyl, sub-pyridazinyl or sub-thienyl, and described group can be selected from following substituting group and replace by one or more: halogen, methyl, methoxyl group and CF 3;
E is NR 5or CH 2, R wherein 5h or C 1-C 3-alkyl;
Ar is selected from following cyclic group: phenyl, comprise 1,2 or 3 and be selected from the heteroatoms of N, O and S as 5 or 6 yuan of heteroaryls of ring members, with with saturated or unsaturated 5 or 6 yuan of carbocyclic rings or heterocyclic fused benzyl ring, wherein said heterocycle comprises 1,2 or 3 heteroatoms independently selected from N, O and S and/or 1,2 or 3 and is selected from NR 8containing heteroatom group as ring members, R wherein 8h, C 1-C 4-alkyl, fluoro C 1-C 4-alkyl, C 1-C 4-alkyl-carbonyl or fluoro C 1-C 4-alkyl-carbonyl, and 1,2 or 3 substituent R of cyclic group Ar portability wherein a;
R ahalogen, C 1-C 6-alkyl, fluoro C 1-C 6-alkyl, C 1-C 6-hydroxyalkyl, C 1-C 6-alkoxy-C 1-C 6-alkyl, C 2-C 6-alkenyl, fluoro C 2-C 6-alkenyl, C 3-C 6-cycloalkyl, fluoro C 3-C 6-cycloalkyl, C 1-C 6-alkoxyl group, C 1-C 6-hydroxy alkoxy base, C 1-C 6-alkoxy-C 1-C 6-alkoxyl group, fluoro C 1-C 6-alkoxyl group, C 1-C 6-alkylthio, fluoro C 1-C 6-alkylthio, C 1-C 6-alkyl sulphinyl, fluoro C 1-C 6-alkyl sulphinyl, C 1-C 6-alkyl sulphonyl, fluoro C 1-C 6-alkyl sulphonyl, phenyl sulfonyl, benzyloxy, phenoxy group, wherein in the end the phenyl in 3 groups can be unsubstituted or portability 1-3 be selected from C 1-C 4-alkyl, fluoro C 1-C 4the substituting group of-alkyl and halogen, or R acN, nitro, C 1-C 6-alkyl-carbonyl, fluoro C 1-C 6-alkyl-carbonyl, C 1-C 6-alkyl-carbonyl-amino, fluoro C 1-C 6-alkyl-carbonyl-amino, carboxyl, NH-C (O)-NR 6r 7, NR 6r 7, NR 6r 7-C 1-C 6-alkylidene group, O-NR 6r 7, R wherein 6and R 7be H, C independently of one another 1-C 4-alkyl, fluoro C 1-C 4-alkyl or C 1-C 4-alkoxyl group, or can form 4,5 or 6 yuan of saturated or unsaturated rings together with N, or R abe saturated or unsaturated 3-7 unit heterocycle, wherein said heterocycle comprises 1,2,3 or 4 heteroatoms that is selected from N, O and S and/or 1,2 or 3 and is selected from NR 9, SO, SO 2with CO containing heteroatom group as ring members, R wherein 9there is one about R 8given implication, and 1,2 or 3 of wherein said heterocycle portabilities are selected from hydroxyl, halogen, C 1-C 6-alkyl, fluoro C 1-C 6-alkyl and C 1-C 6the substituting group of-alkoxyl group.
Therefore, the present invention relates to compound of Formula I and physiology thereof and can tolerate acid salt.
The invention still further relates to pharmaceutical composition, the physiology that described composition comprises at least one formula I compound and/or at least one formula I compound can tolerate acid salt, and physiology can be accepted carrier and/or auxiliary substance if appropriate.
The invention still further relates to treatment to dopamine D 3receptor antagonist or dopamine D 3the method of the illness that the impact of agonist reacts, described method comprises to having at least one formula I compound of individual effective dosage and/or the physiology of at least one formula I compound of these needs can tolerate acid salt.
Detailed Description Of The Invention
To dopamine D 3the illness that the impact of receptor antagonist or agonist reacts comprises, particularly, the disease of central nervous system and illness, particularly affective disorder, neurosis disorder, stress disorder and body type obstacle and psychosis, particularly schizophrenia and dysthymia disorders, and in addition, renal tubal dysfunction, the renal tubal dysfunction especially being caused by diabetes (referring to WO 00/67847).
According to the present invention, at least one compound of Formula I with the described implication of beginning can be used for treating above-mentioned indication.If giving the formula I compound of fixed structure can arrange and exist with different spaces, for example, if they have one or more asymmetric centers, polysubstituted ring or two key or as different tautomers, can also use mixture of enantiomers, particularly racemic modification, non-enantiomer mixture and tautomers mixture, yet each that preferably uses formula I compound be pure enantiomorph, diastereomer and tautomer and/or its salt substantially.
That particularly, carries group A can have (S) or (R) configuration containing the carbon atom of azo-cycle.Yet (S) configuration is preferred.
In addition, with respect to substituent R 2, R 3or R 4(if at least one in them is not hydrogen), group A can be in cis or trans position.Yet cis position is preferred.
Can use equally the physiology of formula I compound can tolerate salt, especially can tolerate with physiology the acid salt that acid forms.It is hydrochloric acid that suitable physiology can tolerate organic and example mineral acid, Hydrogen bromide, phosphoric acid, sulfuric acid, C 1-C 4-alkylsulphonic acid is methylsulfonic acid for example, and aromatic sulfonic acid is Phenylsulfonic acid and toluenesulphonic acids for example, oxalic acid, toxilic acid, fumaric acid, lactic acid, tartrate, hexanodioic acid and phenylformic acid.Other spendable acid is described in Fortschritte der Arzneimittelforschung[Advances in drugresearch], Volume 10, pages 224 ff., verlag, Basel andStuttgart, in 1966.
For each group integral part of listing separately, the organic moiety of mentioning in the definition of above-mentioned variable is-as term halogen-be generic term.Prefix C n-C mrepresent in all cases carbon atom number possible in group.
Term halogen represents fluorine, bromine, chlorine or iodine, particularly fluorine, chlorine or bromine in all cases.
C 1-C 4alkyl is the straight or branched alkyl with 1-4 carbon atom.The example of alkyl is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, 2-butyl, isobutyl-or the tertiary butyl.C 1-C 2alkyl is methyl or ethyl, C 1-C 3alkyl or n-propyl or sec.-propyl.
C 1-C 6alkyl is the straight or branched alkyl with 1-6 carbon atom.Example comprises above-mentioned C 1-C 4alkyl and amyl group, 1-methyl butyl, 2-methyl butyl, 3-methyl butyl, 2, 2-dimethyl propyl, 1-ethyl propyl, hexyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, 1-methyl amyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethyl-butyl, 2-ethyl-butyl, 1, 1, 2-trimethylammonium propyl group, 1, 2, 2-trimethylammonium propyl group, 1-ethyl-1-methyl-propyl and 1-Ethyl-2-Methyl propyl group.
Fluoro C 1-C 6alkyl is to have 1-6, especially 1-4, the straight or branched alkyl of 1-3 carbon atom particularly, wherein at least one, for example 1, 2, 3, 4 or all hydrogen atoms by fluorine atom, replaced, for example, in following groups: methyl fluoride, difluoromethyl, trifluoromethyl, (R)-1-fluoro ethyl, (S)-1-fluoro ethyl, 2-fluoro ethyl, 1,1-, bis-fluoro ethyls, 2,2-, bis-fluoro ethyls, 2,2,2-trifluoroethyl, (R)-1-fluoropropyl, (S)-1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1,1-, bis-fluoropropyls, 2,2-, bis-fluoropropyls, 3,3-, bis-fluoropropyls, 3,3,3-trifluoro propyl, (R) the fluoro-1-methylethyl of-2-, (S) the fluoro-1-methylethyl of-2-, (R)-2, the fluoro-1-methylethyl of 2-bis-, (S)-2, the fluoro-1-methylethyl of 2-bis-, (R)-1, the fluoro-1-methylethyl of 2-bis-, (S)-1, the fluoro-1-methylethyl of 2-bis-, (R)-2,2, the fluoro-1-methylethyl of 2-tri-, (S)-2,2, the fluoro-1-methylethyl of 2-tri-, the fluoro-1-of 2-(methyl fluoride) ethyl, 1-(difluoromethyl)-2,2-bis-fluoro ethyls, 1-(trifluoromethyl)-2,2,2-trifluoroethyl, 1-(trifluoromethyl)-1,2,2,2-tetrafluoro ethyl, (R)-1-fluorine butyl, (S)-1-fluorine butyl, 2-fluorine butyl, 3-fluorine butyl, 4-fluorine butyl, 1,1-difluoro butyl, 2,2-difluoro butyl, 3,3-difluoro butyl, 4,4-difluoro butyl, 4,4,4-trifluoro butyl etc.
Side chain C 3-C 6alkyl is the alkyl with 3-6 carbon atom, and wherein at least one carbon atom is the second month in a season or tertiary carbon atom.Example is sec.-propyl, the tertiary butyl, 2-butyl, isobutyl-, 2-amyl group, 2-hexyl, 3-methyl amyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1-methyl isophthalic acid-ethyl propyl.
Fluoro side chain C 3-C 6alkyl is the alkyl with 3-6 carbon atom, and wherein at least one carbon atom is the second month in a season or tertiary carbon atom, and wherein at least one, for example 1,2,3,4 or all hydrogen atoms by fluorine atom, replaced.
C 1-C 6alkoxyl group is to have 1-6, and particularly 1-4 carbon atom, is bonded in the straight or branched alkyl on molecule rest part via Sauerstoffatom.The example comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, 2-butoxy, isobutoxy, tert.-butoxy, pentyloxy, 1-methyl butoxy, 2-methyl butoxy, 3-methyl butoxy, 2, 2-dimethyl propoxy-, 1-ethyl propoxy-, hexyloxy, 1, 1-dimethyl propoxy-, 1, 2-dimethyl propoxy-, 1-methyl pentyloxy, 2-methyl pentyloxy, 3-methyl pentyloxy, 4-methyl pentyloxy, 1, 1-dimethyl butoxy, 1, 2-dimethyl butoxy, 1, 3-dimethyl butoxy, 2, 2-dimethyl butoxy, 2, 3-dimethyl butoxy, 3, 3-dimethyl butoxy, 1-ethyl butoxy, 2-ethyl butoxy, 1, 1, 2-trimethylammonium propoxy-, 1, 2, 2-trimethylammonium propoxy-, 1-ethyl-1-methyl propoxy-and 1-Ethyl-2-Methyl propoxy-.
Fluoro C 1-C 6alkoxyl group is to have 1-6, the straight or branched alkoxyl group of 1-4 carbon atom particularly, wherein at least one, for example 1, 2, 3, 4 or all hydrogen atoms by fluorine atom, replaced, for example, in following groups: fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, (R)-1-fluorine oxyethyl group, (S)-1-fluorine oxyethyl group, 2-fluorine oxyethyl group, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoro ethoxy, (R)-1-fluorine propoxy-, (S)-1-fluorine propoxy-, (R)-2-fluorine propoxy-, (S)-2-fluorine propoxy-, 3-fluorine propoxy-, 1,1-difluoro propoxy-, 2,2-difluoro propoxy-, 3,3-difluoro propoxy-, 3,3,3-trifluoro propoxy-, (R) the fluoro-1-methyl ethoxy of-2-, (S) the fluoro-1-methyl ethoxy of-2-, (R)-2, the fluoro-1-methyl ethoxy of 2-bis-, (S)-2, the fluoro-1-methyl ethoxy of 2-bis-, (R)-1, the fluoro-1-methyl ethoxy of 2-bis-, (S)-1, the fluoro-1-methyl ethoxy of 2-bis-, (R)-2,2, the fluoro-1-methyl ethoxy of 2-tri-, (S)-2,2, the fluoro-1-methyl ethoxy of 2-tri-, the fluoro-1-of 2-(methyl fluoride) oxyethyl group, 1-(difluoromethyl)-2,2-difluoroethoxy, (R)-1-fluorine butoxy, (S)-1-fluorine butoxy, 2-fluorine butoxy, 3-fluorine butoxy, 4-fluorine butoxy, 1,1-difluoro butoxy, 2,2-difluoro butoxy, 3,3-difluoro butoxy, 4,4-difluoro butoxy, 4,4,4-trifluoro butoxy etc.
C 1-C 6hydroxyalkyl is to have 1-6, especially 1-4, and the straight or branched alkyl of 1-3 carbon atom particularly, one of them hydrogen atom is substituted by hydroxyl, for example, in 2-hydroxyethyl or 3-hydroxypropyl.
C 1-C 6-alkoxy-C 1-C 6-alkyl is to have 1-6, especially 1-4, and the straight or branched alkyl of 1-3 carbon atom particularly, one of them hydrogen atom is by C 1-C 6-alkoxyl group replaces, such as in following groups: methoxymethyl, 2-methoxy ethyl, ethoxyl methyl, 3-methoxy-propyl, 3-ethoxycarbonyl propyl etc.
C 1-C 6-alkoxy-C 1-C 6-alkoxyl group is to have 1-6, especially 1-4, and the straight or branched alkyl of 1-3 carbon atom particularly, one of them hydrogen atom is by C 1-C 6-alkoxyl group base replaces, such as in following groups: 2-methoxy ethoxy, oxyethyl group methoxy base, 2-ethoxy ethoxy, 3-methoxy propoxy, 3-oxyethyl group propoxy-etc.
C 1-C 6-alkyl-carbonyl is to have 1-6, especially 1-4, and the straight or branched alkyl of 1-3 carbon atom particularly, one of them hydrogen atom for example, by carbonyl (CO) replacement, in ethanoyl and propionyl.
Fluoro C 1-C 6-alkyl-carbonyl is to have 1-6; especially 1-4; the straight or branched alkyl of 1-3 carbon atom particularly; one of them hydrogen atom is replaced by carbonyl (CO); and wherein at least one, for example 1,2,3,4 or all hydrogen atoms by fluorine atom, replaced, for example, in trifluoroacetyl group and 3; in 3,3-trifluoropropyl acyl group.
C 1-C 6-alkyl-carbonyl-amino is to have 1-6, especially 1-4, and the straight or branched alkyl of 1-3 carbon atom particularly, one of them hydrogen atom is by carbonylamino (CO-NH-) replacement, for example, at kharophen (CH 3cONH-) and propionamido (CH 3cH 2cONH-) in.
Fluoro C 1-C 6-alkyl-carbonyl-amino is to have 1-6; especially 1-4; the straight or branched alkyl of 1-3 carbon atom particularly; one of them hydrogen atom is replaced by carbonylamino (CO-NH-); and at least one all the other hydrogen atom wherein, for example 1,2,3 or 4 hydrogen atom is replaced by fluorine atom, for example, in trifluoroacetyl group and 3; in 3,3-trifluoropropyl acyl group.
C 1-C 6alkylthio (is also called C 1-C 6-alkyl sulfenyl) (or difference C 1-C 6-alkyl sulphinyl or C 1-C 6-alkyl sulphonyl) refer to and there is 1-6, the straight or branched alkyl of 1-4 carbon atom for example, its via the sulphur atom on any key in alkyl (or for alkyl sulphinyl, via S (O) O, or for alkyl sulphonyl, via S (O) 2o) with the rest part bonding of molecule.C 1-C 4the example of-alkylthio comprises methylthio group, ethylmercapto group, rosickyite base, isopropyl sulfenyl and positive butylthio.C 1-C 4the example of-alkyl sulphinyl comprises methylsulfinyl, ethyl sulfinyl, propyl group sulfinyl, sec.-propyl sulfinyl and normal-butyl sulfinyl.C 1-C 4the example of-alkyl sulphonyl comprises methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, sec.-propyl alkylsulfonyl and normal-butyl alkylsulfonyl.
Fluoro C 1-C 6alkylthio (is also called fluoro C 1-C 6-alkyl sulfenyl) be to there is 1-6, the straight or branched alkylthio of 1-4 carbon atom particularly, wherein at least one, for example 1,2,3,4 or all hydrogen atoms by fluorine atom, replaced.Fluoro C 1-C 6alkyl sulphinyl is to have 1-6, the straight or branched alkyl sulphinyl of 1-4 carbon atom particularly, wherein at least one, for example 1,2,3,4 or all hydrogen atoms by fluorine atom, replaced.Fluoro C 1-C 6alkyl sulphonyl is to have 1-6, the straight or branched alkyl sulphonyl of 1-4 carbon atom particularly, wherein at least one, for example 1,2,3,4 or all hydrogen atoms by fluorine atom, replaced.
C 3-C 6cycloalkyl is the alicyclic group with 3-6 carbon atom, for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Cycloalkyl can be unsubstituted or can carry 1,2,3 or 4 C 1-C 4alkyl, preferable methyl.An alkyl is preferably placed at the 1-position of cycloalkyl, for example 1-methyl cyclopropyl or 1-methyl cyclobutyl.
Fluoro C 3-C 6cycloalkyl is the alicyclic group with 3-6 carbon atom, cyclopropyl for example, cyclobutyl, cyclopentyl and cyclohexyl, wherein at least one, for example 1, 2, 3, 4 or all hydrogen atoms by fluorine atom, replaced, for example, in following groups: 1-fluorine cyclopropyl, 2-fluorine cyclopropyl, (S)-and (R)-2, 2-difluoro cyclopropyl, 1, 2-difluoro cyclopropyl, 2, 3-difluoro cyclopropyl, five fluorine cyclopropyl, 1-fluorine cyclobutyl, 2-fluorine cyclobutyl, 3-fluorine cyclobutyl, 2, 2-difluoro cyclobutyl, 3, 3-difluoro cyclobutyl, 1, 2-difluoro cyclobutyl, 1, 3-difluoro cyclobutyl, 2, 3-difluoro cyclobutyl, 2, 4-difluoro cyclobutyl or 1, 2, 2-trifluoro cyclobutyl.
C 2-C 6-alkenyl is the cholesterol alkyl with 2,3,4,5 or 6 carbon atoms, for example vinyl, allyl group (2-propylene-1-yl), 1-propylene-1-base, 2-propylene-2-base, methylallyl (2-methyl-prop-2-alkene-1-yl) etc.C 3-C 6-alkenyl is allyl group, 1-methyl-prop-2-alkene-1-base, 2-butylene-1-base, 3-butene-1-Ji, methylallyl, 2-amylene-1-base, 3-amylene-1-base, 4-amylene-1-base, 1-methyl but-2-ene-1-base or 2-ethyl third-2-alkene-1-base particularly.
Fluoro C 2-C 6-alkenyl is the cholesterol alkyl with 2,3,4,5 or 6 carbon atoms, wherein at least one, for example 1,2,3,4 or all hydrogen atoms by fluorine atom, replaced, for example, in following groups: 1-is fluoride-based, 2-is fluoride-based, 2,2-is fluoride-based, 3,3,3-fluorine propenyl, 1, the fluoro-2-propenyl of the fluoro-2-propenyl of 1-bis-1-etc.
C 1-C 6-alkylidene group is the hydrocarbon abutment with 1,2,3,4,5 or 6 carbon atom, for example methylene radical, ethylidene, 1,2-and trimethylene, tetramethylene etc.
The example of 5 or 6 yuan of heteroaromatic group comprises 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, pyrazinyl, 3-or 4-pyridazinyl, 2-or 3-thienyl, 2-or 3-furyl, 2-or 3-pyrryl, 2-, 3-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 2-, 3-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-imidazolyl, 2-or 5-[1, 3, 4] oxadiazolyls, 4-or 5-[1, 2, 3] oxadiazolyls, 3-or 5-[1, 2, 4] oxadiazolyls, 2-or 5-[1, 3, 4] thiadiazolyl group, 2-or 5-[1, 3, 4] thiadiazolyl group, 4-or 5-[1, 2, 3] thiadiazolyl group, 3-or 5-[1, 2, 4] thiadiazolyl group 1H-, 2H-or 3H-1, 2, 3-triazole-4-yl, 2H-triazole-3-base, 1H-, 2H-or 4H-1, 2, 4-triazolyl and 1H-or 2H-tetrazyl, described group can be unsubstituted or can carry 1, 2 or 3 above-mentioned radicals R a.
Comprise indenyl, indanyl, naphthyl, 1 with the example of saturated or unsaturated 5 or 6 yuan of carbocyclic rings or heterocyclic fused phenyl, 2-or 2,3-dihydro naphthyl, naphthane, benzofuryl, 2,3-dihydro benzo furyl, benzothienyl, indyl, indazolyl, benzimidazolyl-, Ben Bing Evil thiazolyl, Ben Bing oxadiazolyl, diazosulfide base, benzoxazinyl, Er hydrogen benzoxazinyl, cinnolines base, different cinnolines base, the different cinnolines base of tetrahydrochysene, chromenyl, chromanyl etc., described group can be unsubstituted or can carry 1,2 or 3 above-mentioned radicals R a.This condenses system can be via the carbon atom of phenyl moiety or via the ring members (C-or N-atom) of ring and rest part (more definitely saying and the alkylsulfonyl) bonding of molecule that condense with phenyl.
The first heterocycle of saturated or unsaturated 3-7 is (as radicals R a) example comprise saturated or unsaturated, aromatics or non-aromatic heterocyclic.Except 5 or 6 yuan of heteroaryls defined above, the example comprises ethylenimine base, diazacyclo propyl, oxirane base, azetidinyl, azetidin thiazolinyl, dihydrofuran base and tetrahydrofuran base, pyrrolinyl, pyrrolidyl, oxo-pyrrolidine base, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, oxazolinyl, oxazolidinyl, oxo-oxazolidinyl, isoxazoline-3-yl, isoxazole alkyl, piperidyl, piperazinyl, morpholinyl etc.
If R 6and R 7form 4-, 5-or 6-ring together with N, except defined above, contain 5 or 6 yuan of heteroaryls of at least one N atom as ring members, the example of this class group comprises azetidinyl, azetidin thiazolinyl, pyrrolinyl, pyrrolidyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, oxazolinyl, oxazolidinyl, piperidyl, piperazinyl, morpholinyl etc.
In a specific embodiments,
R 1h, can be by C 3-C 6the C of-cycloalkyl substituted 1-C 6-alkyl, fluoro C 1-C 6-alkyl, C 3-C 6-cycloalkyl, fluoro C 3-C 6-cycloalkyl, C 3-C 6-alkenyl, fluoro C 3-C 6-alkenyl, formyl radical, ethanoyl or propionyl; And
Ar is selected from following cyclic group: phenyl, comprise 1,2 or 3 and be selected from the heteroatoms of N, O and S as 5 or 6 yuan of heteroaryls of ring members, with with saturated or unsaturated 5 or 6 yuan of carbocyclic rings or heterocyclic fused benzyl ring, wherein said heterocycle comprises 1,2 or 3 heteroatoms that is selected from N, O and S as ring members, and wherein 1,2 or 3 of this cyclic group portabilities are selected from following substituent R a: halogen, C 1-C 6-alkyl, fluoro C 1-C 6-alkyl, C 3-C 6-cycloalkyl, fluoro C 3-C 6-cycloalkyl, C 1-C 6-alkoxyl group, fluoro C 1-C 6-alkoxyl group, CN, ethanoyl, carboxyl, NR 6r 7, NR 6r 7-C 1-C 6-alkylidene group and saturated or unsaturated 5 or 6 yuan of heterocycles, wherein said heterocycle comprises 1,2 or 3 heteroatoms that is selected from N, O and S as ring members, wherein R 6and R 7be H, C independently of one another 1-C 4-alkyl or fluoro C 1-C 4-alkyl, or can form 4,5 or 6 yuan of saturated or unsaturated rings together with N.
In formula I compound, n preferably 0 or 1; Containing azo-cycle, be azetidinyl or pyrrolidyl; N particularly 1, this means in particularly preferred embodiments, and nitrogen heterocyclic ring is tetramethyleneimine basic ring.
Preferably, radicals R 1be selected from H, C 1-C 4-alkyl, by C 3-C 6the C that-cycloalkyl or hydroxyl replace 1-C 4-alkyl, fluoro C 1-C 4-alkyl and C 2-C 4-alkenyl.More preferably H, propyl group, cyclopropyl methylene radical, fluoro ethyl is 2-fluoro ethyl for example, and fluoro propyl group is 3-fluoropropyl for example, and hydroxypropyl is 3-hydroxypropyl for example, propionyl and allyl group.More preferably, R 1be selected from H, propyl group, cyclopropyl methylene radical, 2-fluoro ethyl, 3-fluoropropyl, 3-hydroxypropyl and allyl group.In a more preferred embodiment, R 1n-propyl or allyl group, and n-propyl especially.
In another embodiment, R 1be preferably selected from H, C 1-C 4-alkyl, by C 3-C 6the C of-cycloalkyl substituted 1-C 4-alkyl, fluoro C 1-C 4-alkyl and C 2-C 4-alkenyl.More preferably H, propyl group, cyclopropyl methylene radical, fluoro ethyl is 2-fluoro ethyl for example, and fluoro propyl group is 3-fluoropropyl for example, and allyl group.In particularly preferred embodiments, R 1n-propyl or allyl group, especially n-propyl.
Preferably, R 2, R 3and R 4h.
Group A is phenylene, pyridylidene or sub-pyrimidyl preferably.In a more preferred embodiment, A is Isosorbide-5-Nitrae-phenylene, 1,2-phenylene, 2, and 5-pyridylidene, 3, the sub-pyrimidyl of 6-pyridylidene or 2,5-, wherein A can be substituted as mentioned above.In even preferred embodiment, A is Isosorbide-5-Nitrae-phenylene, 1,2-phenylene, 3, the sub-pyrimidyl of 6-pyridylidene or 2,5-.If A is substituted, preferred substituting group is selected from halogen, particularly fluorine, and methoxyl group.Example comprises the fluoro-Isosorbide-5-Nitrae-phenylene of 2-, the fluoro-Isosorbide-5-Nitrae-phenylene of 3-, 2-methoxyl group-Isosorbide-5-Nitrae-phenylene and 3-methoxyl group-Isosorbide-5-Nitrae-phenylene.In a specific embodiments, A is not substituted.A is Isosorbide-5-Nitrae-phenylene.
Group E is NR preferably 5, be more preferably NH or NCH 3, NH particularly.
Preferred cyclic group Ar is phenyl, 2-or 3-thienyl, particularly 3-thienyl, imidazolyl, particularly 4-imidazolyl, isoxazolyl, particularly 4-isoxazolyl, thiazolyl, particularly 2-thiazolyl, triazolyl, particularly 3-[1,2,4] triazolyl, thiadiazolyl group, particularly 3-and 5-[1,2,4] thiadiazolyl group and 2-[1,3,4] thiadiazolyl group, 2-, 3-or 4-pyridyl, 2-and 5-pyrimidyl, 1-, 2-, 3-, 4-or 5-indanyl, 2-, 3-, 4-or 5-benzofuryl, quinolyl, particularly 8-quinolyl, isoquinolyl, particularly 5-isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, particularly 7-1,2,3,4-tetrahydroisoquinoline-7-base, benzothienyl, 2-benzothienyl particularly, benzothiazolyl, particularly 6-benzothiazolyl, Ben Bing oxadiazolyl, 4-[2 particularly, 1,3] Ben Bing oxadiazolyl, diazosulfide base, 4-[2 particularly, 1,3] diazosulfide base, benzoxazine and Er hydrogen benzoxazine.The position of numeral Ar and alkylsulfonyl bonding.Preferred group Ar is phenyl, 2-thienyl, 3-pyridyl, 5-pyridyl, 5-indanyl, 2-benzofuryl and 2,3-Dihydrobenzofuranes-2-base.Even preferred group Ar is phenyl, 2-thienyl, 5-indanyl, cumarone-2-base and 2,3-Dihydrobenzofuranes-2-base.Specifically, Ar is phenyl.
In another embodiment, preferred cyclic group Ar is phenyl, 2-or 3-thienyl, 2-, 3-or 4-pyridyl, 1-, 2-, 3-, 4-or 5-indanyl, 2-, 3-, 4-or 5-benzofuryl, particularly 2-thienyl, 2-or 3-pyridyl, 5-indanyl, 5-benzofuryl and especially phenyl.
Preferably, R abe selected from halogen, C 1-C 6-alkyl, fluoro C 1-C 6-alkyl, C 1-C 6-hydroxyalkyl, C 1-c 6-alkoxy-C 1-C 6-alkyl, C 2-C 6-alkenyl, C 3-C 6-cycloalkyl, fluoro C 3-C 6-cycloalkyl, C 1-C 6-alkoxyl group, C 1-C 6-alkoxy-C 1-C 6-alkoxyl group, fluoro C 1-C 6-alkoxyl group, fluoro C 1-C 6-alkylthio, C 1-C 6-alkyl sulphonyl, phenyl sulfonyl, benzyloxy, phenoxy group, CN, nitro, ethanoyl, trifluoroacetyl group, kharophen, carboxyl, NH-C (O)-NH 2, NR 6r 7, NR 6r 7-C 1-C 6-alkylidene group, O-NR 6r 7, R wherein 6and R 7be H, C independently of one another 1-C 4-alkyl, fluoro C 1-C 4-alkyl or C 1-C 4-alkoxyl group, and saturated or unsaturated 3-7 unit heterocycle, wherein said heterocycle comprises 1,2,3 or 4 heteroatoms that is selected from N, O and S and/or 1,2 or 3 and is selected from NR 9, SO, SO 2with CO containing heteroatom group as ring members, R wherein 9there is one about R 8given implication, and 1,2 or 3 of wherein said 3-7 unit heterocycle portabilities are selected from hydroxyl, halogen, C 1-C 6-alkyl, fluoro C 1-C 6-alkyl and C 1-C 6the substituting group of-alkoxyl group.
Preferably, the first heterocycle of saturated or unsaturated 3-7 is selected from azetidine-1-base, 2-methyl azetidine base, 3-methoxyl group azetidinyl, 3-hydroxy azetidine base, 3-fluorine azetidinyl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 2-and 3-fluoropyrrolidine-1-base, 2,2-difluoro pyrrolidin-1-yl, 3,3-difluoro pyrrolidin-1-yl, 2-and 3-methylpyrrolidin-1-base, 1-methylpyrrolidin-2-base, 2,2-dimethyl pyrrolidine-1-base 3,3-dimethyl pyrrolidine-1-base, 2-oxo-pyrrolidin-1-yl, 2-and 3-trifluoromethyl pyrpole alkane-1-base, 2-oxo-oxazolidines-1-base, piperidin-1-yl, pipecoline-1-base, piperazine-1-base, 4-methylpiperazine-1-yl, morpholine-4-base, thiomorpholine-4-base, 1-oxo thiomorpholine-4-base, 1,1-dioxo thiomorpholine-4-base, pyrroles-1-base, pyrroles-2-base, pyrroles-3-base, 1-methylpyrrole-2-base, 1-methylpyrrole-3-base, furans-2-base, furans-3-base, thiophene-2-base, thiene-3-yl-, 5-rosickyite base benzene-2-base, pyrazol-1-yl, pyrazole-3-yl, pyrazoles-4-base, 1-methyl-pyrazol-4-yl, imidazoles-1-base, imidazoles-2-base, 1-Methylimidazole-2-base, oxazole-2-base, oxazole-4-base, oxazole-5-base, isoxazole-3-base, isoxazole-4-base, isoxazole-5-base, [1,2,3] triazol-1-yl, [1,2,4] triazol-1-yl, [1,2,3] triazole-2-base, [1,2,4] triazole-3-base, [1,2,4] triazole-4-yl, 4-methyl-[1,2,4] triazole-3-base, 2-methyl-[1,2,3] triazole-4-yl, [1,3,4]-oxadiazoles-2-base, [1,2,4]-oxadiazoles-3-base, [1,2,4]-oxadiazoles-5-base, [1,2,3]-oxadiazoles-5-base, [1,2,3] thiadiazoles-4-base, tetrazolium-1-base, tetrazolium-5-base, 2-methyl tetrazolium-5-base, 1-methyl tetrazolium-5-base, furazan-3-base, pyridine-2-base, pyridin-3-yl, pyridin-4-yl, pyrimidine-2-base, pyrimidine-4-yl and pyrimidine-5-base.More preferably, the first heterocycle of saturated or unsaturated 3-7 is selected from azetidine-1-base, pyrrolidin-1-yl, 3,3-difluoro pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2-oxo-oxazolidines-1-base, morpholine-4-base, 2-furyl, 5-propyl group thiophene-2-base, pyrroles-1-base, pyrazol-1-yl, 1-methyl-pyrazol-4-yl, 1-ethyl pyrazoles-4-Ji, oxazole-5-base, isoxazole-3-base, isoxazole-5-base, 4-[1,2,3] thiadiazolyl group.Even more preferably, the first heterocycle of saturated or unsaturated 3-7 is selected from azetidine-1-base, pyrrolidin-1-yl, 3,3-difluoro pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, morpholine-4-base, pyrroles-1-base, furans-2-base, pyrazol-1-yl, 1-methyl-pyrazol-4-yl, oxazole-5-base, isoxazole-5-base, 4-[1,2,3] thiadiazolyl group.
In preferred embodiments, cyclic group Ar is unsubstituted or is selected from following substituent R by 1,2 or 3 areplace: halogen, C 1-C 6-alkyl, C 1-C 6-hydroxyalkyl, fluoro C 1-C 4-alkyl, C 1-C 4-alkoxyl group, fluoro C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 4-alkenyl, fluoro C 2-C 4-alkenyl, NR 6r 7, ONR 6r 7, C 1-C 6-alkylidene group-NR 6r 7, R wherein 6and R 7be H, C independently of one another 1-C 4-alkyl or C 1-C 4-alkoxyl group, urea groups (NHCONH 2) C 3-C 6-cycloalkyl, fluoro C 3-C 6-cycloalkyl, ethanoyl, carboxyl, hydroxyl, cyano group, nitro, benzoyloxy, methylthio group, fluorine methylthio group, difluoro methylthio group, trifluoromethylthio, methyl sulphonyl and an above-mentioned saturated or first heterocycle of unsaturated 3-7.In a more preferred embodiment, R abe selected from halogen, C 1-C 6-alkyl, fluoro C 1-C 4-alkyl, C 1-C 4-alkoxyl group, OCF 3, OCHF 2, OCH 2f, C 2-C 4-alkenyl, C 3-C 6-cycloalkyl, fluoro C 3-C 6-cycloalkyl, urea groups, ethanoyl, carboxyl, hydroxyl, cyano group, benzoyloxy, trifluoromethylthio, methyl sulphonyl, ammonia heterocycle butane-1-base, pyrrolidin-1-yl, 3,3-difluoro pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2-oxo- azoles alkane-1-base, morpholine-4-base, 2-furyl, 5-propyl group thiophene-2-base, pyrroles-1-base, pyrazol-1-yl, 1-methyl-pyrazol-4-yl, 1-ethyl pyrazoles-4-base, azoles-5-base, different azoles-3-base, different azoles-5-base and 4-[1,2,3] thiadiazolyl group.Even more preferably, R abe selected from halogen, C 1-C 6-alkyl, fluoro C 1-C 4-alkyl, C 1-C 4-alkoxyl group, OCF 3, OCHF 2, C 2-C 4-alkenyl, C 3-C 6-cycloalkyl, fluoro C 3-C 6-cycloalkyl, urea groups, ethanoyl, carboxyl, hydroxyl, benzoyloxy, trifluoromethylthio, azetidine-1-base, pyrrolidin-1-yl, 3,3-difluoro pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, morpholine-4-base, pyrroles-1-base, furans-2-base, pyrazol-1-yl, 1-methyl-pyrazol-4-yl, azoles-5-base, different azoles-5-base and 4-[1,2,3] thiadiazolyl group.
If Ar is hetero-aromatic ring, in this case, R abe selected from especially halogen, C 2-C 4-alkenyl, azoles base and different azoles base.If Ar condenses system, rise preferably and be not substituted.
In another embodiment, cyclic group is selected from following substituent R by 1,2 or 3 areplace: halogen, C 1-C 6-alkyl, fluoro C 1-C 4-alkyl, C 1-C 4-alkoxyl group, fluoro C 1-C 4-alkoxyl group, C 2-C 4-alkenyl, fluoro C 2-C 4-alkenyl, NR 6r 7, C 1-C 6-alkylidene group-NR 6r 7, R wherein 6and R 7be H, C independently of one another 1-C 4-alkyl or fluoro C 1-C 4-alkyl, or can form for example CH of 4,5 or 6 yuan of saturated or unsaturated rings together with N 2n (CH 3) 2, C 3-C 6-cycloalkyl, described cycloalkyl is optionally by halogen, ethanoyl or carboxyl substituted.In a more preferred embodiment, Ar is phenyl, and described phenyl is selected from following substituting group by 1,2 or 3 and replaces: halogen, C 1-C 6-alkyl, fluoro C 1-C 4-alkyl, C 1-C 4-alkoxyl group, OCF 3, OCHF 2, OCH 2f, C 2-C 4-alkenyl, fluoro C 2-C 4-alkenyl, CH 2n (CH 3) 2, NR 6r 7, the C that optionally replaced by halogen 3-C 6-cycloalkyl, ethanoyl or carboxyl, wherein R 6and R 7be H, C independently of one another 1-C 4-alkyl or fluoro C 1-C 4-alkyl, or Ar is thienyl, pyridyl, benzofuryl or indanyl, and described group is optionally by halogen, C 1-C 4-alkyl or C 1-C 4-alkenyl replaces.More preferably, Ar is phenyl, and described phenyl is selected from following substituent R by 1,2 or 3 areplace: fluorine or bromine, C 1-C 6-alkyl, especially methyl, ethyl, n-propyl, sec.-propyl, sec-butyl, isobutyl-, dimethyl propyl and particularly sec.-propyl, fluoro C 1-C 4-alkyl, especially CF 3or fluoro sec.-propyl, C 1-C 4-alkoxyl group, especially methoxyl group, oxyethyl group, propoxy-, isopropoxy or butoxy, OCF 3, OCHF 2, OCH 2f, pseudoallyl, CH 2n (CH 3) 2, NR 6r 7, R wherein 6and R 7be H, C independently of one another 1-C 4-alkyl or fluoro C 1-C 4-alkyl, C 3-C 6-cycloalkyl, especially cyclopentyl, fluoro C 3-C 6-cycloalkyl, especially 2,2-difluoro cyclopropyl, ethanoyl or carboxyl.Or Ar is thienyl or pyridyl, described group carries 1,2 or 3 and is selected from following substituting group: halogen, especially chlorine, and C 1-C 4-alkenyl, especially pseudoallyl, or Ar is benzofuryl or indanyl.
In above-mentioned 5 yuan of heteroaromatic group, Ar preferably (relates to SO in 5-position 2the 2-position of-group) carry a radicals R a, and optionally one or two is selected from halogen, particularly the other group of fluorine or chlorine.
Phenyl and above-mentioned 6 yuan of heteroaromatic group preferably (relate to SO in 4-position 2the 1-position of-group) carry a radicals R a, and optionally one or two is selected from halogen, particularly the other group of fluorine or chlorine.
In highly preferred embodiment of the present invention, Ar is phenyl, and described phenyl carries a radicals R in the 4-position of this benzyl ring a, and optional 1 or 2 halogen atom, described halogen atom is selected from halogen, is particularly selected from fluorine or chlorine.
In even preferred embodiment, Ar preferably carries a radicals R a, it has formula R a '
Wherein
Y is N, CH or CF,
R a1and R a2be independently from each other C 1-C 2-alkyl, particularly methyl, fluoro C 1-C 2-alkyl, particularly methyl fluoride, difluoromethyl or trifluoromethyl, condition is: when Y is CH or CF, a radicals R a1or R a2can also be hydrogen or fluorine, or
R a1and R a2form group (CH 2) m, wherein 1 or 2 hydrogen atom can be replaced by fluoro, and wherein m is 2,3 or 4, particularly CH 2-CH 2, CHF-CH 2, CF 2-CH 2, CH 2-CH 2-CH 2, CHF-CH 2-CH 2, CF 2-CH 2-CH 2, CH 2-CHF-CH 2, CH 2-CF 2-CH 2.
Work as R a1and R a2while differing from one another, about Y-part, the group of above-mentioned formula Ra can have (R)-or (S)-configuration.
Preferred formula R a 'the example of group comprises sec.-propyl, (R)-1-fluoro ethyl, (S)-1-fluoro ethyl, 2-fluoro ethyl, 1, 1-bis-fluoro ethyls, 2, 2-bis-fluoro ethyls, 2, 2, 2-trifluoroethyl, (R)-1-fluoropropyl, (S)-1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1, 1-bis-fluoropropyls, 2, 2-bis-fluoropropyls, 3, 3-bis-fluoropropyls, 3, 3, 3-trifluoro propyl, (R) the fluoro-1-methylethyl of-2-, (S) the fluoro-1-methylethyl of-2-, (R)-2, the fluoro-1-methylethyl of 2-bis-, (S)-2, the fluoro-1-methylethyl of 2-bis-, (R)-1, the fluoro-1-methylethyl of 2-bis-, (S)-1, the fluoro-1-methylethyl of 2-bis-, (R)-2, 2, the fluoro-1-methylethyl of 2-tri-, (S)-2, 2, the fluoro-1-methylethyl of 2-tri-, the fluoro-1-of 2-(methyl fluoride) ethyl, 1-(difluoromethyl)-2, 2-bis-fluoro ethyls, the fluoro-1-methylethyl of 1-cyclopropyl, cyclobutyl, 1-fluorine cyclopropyl, (S)-and (R)-2, 2-difluoro cyclopropyl and 2-fluorine cyclopropyl.
At formula R a 'in the middle of group, preferred group is to carry 1,2,3 or 4, particularly those of 1,2 or 3 fluorine atom.
In particularly preferred embodiments, radicals R a 'it is the 4-position at benzyl ring.
For the Ar, particularly preferred examples of the following group: 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-isopropyl-phenyl, 4-sec-butylphenyl, 4 - isobutyl-phenyl, 4-(1,1-dimethyl-propyl) - phenyl, 4-vinylphenyl, 4-isopropenylphenyl, 4-fluorophenyl, 4-chlorophenyl , 4-bromophenyl, 4-(trifluoromethyl) phenyl, 3-(trifluoromethyl) phenyl, 2-(fluoromethyl) phenyl, 4-(difluoromethyl) phenyl, 3 (difluoromethyl) phenyl, 2-(difluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, 3-(trifluoromethyl) phenyl, 2-(trifluoromethyl) phenyl, 4-(1-fluoroethyl) - phenyl, 4 - ((S) -1--fluoro-ethyl) - phenyl, 4 - ((R) -1- fluoro-ethyl) - phenyl, 4- (2-fluoroethyl) - phenyl, 4-(1,1-difluoro-ethyl) - phenyl, 4-(2,2-difluoro-ethyl) - phenyl, 4-(2, 2,2-trifluoro-ethyl) - phenyl, 4-(3-fluoro-propyl) - phenyl, 4-(2-fluoro-propyl) - phenyl, 4 - ((S) -2- -fluoropropoxy yl) - phenyl, 4 - ((R) -2- fluoro-propyl) - phenyl, 4-(3,3-difluoro-propyl) - phenyl, 4-(3,3,3-trifluoro- propyl) - phenyl, 4-(1-fluoro-1-methyl-ethyl) - phenyl, 4-(2-fluoro-1-methyl-ethyl) - phenyl, 4 - ((S) - 2-fluoro-1-methyl-ethyl) - phenyl, 4 - ((R) -2--fluoro-1-methyl-ethyl) - phenyl, 4-(2,2-difluoro-1-carboxylic yl-ethyl) - phenyl, 4 - ((S) -2,2--difluoro-1-methylethyl) - phenyl, 4 - ((R) -2,2--difluoro-1-carboxylic yl-ethyl) - phenyl, 4-(2,2,2-trifluoro-1-methylethyl) - phenyl, 4 - ((S) -2,2,2--trifluoro-1-carboxylic yl-ethyl) - phenyl, 4 - ((R) -2,2,2- trifluoro-1-methylethyl) - phenyl, 4-(2-fluoro-l-fluoromethyl-ethyl) - phenyl, 4-(1-fluoromethyl 2,2-difluoro-ethyl) - phenyl, 4-(1,1-dimethyl-2-fluoro-ethyl) - phenyl, 4- methoxyphenyl, 4-ethoxyphenyl, 4-propoxy-phenyl, 4-isopropoxy-phenyl, 4-butoxyphenyl, 4-(trifluoromethoxy) - phenyl 4-(difluoromethoxy) - phenyl, 4-(trifluoromethoxy) - phenyl, 3 - (trifluoromethoxy) - phenyl, 4-(2-fluoro-ethoxy) - phenyl, 4-(2,2-difluoro-ethoxy) - phenyl, 4-(2,2,2-trifluoro-ethoxy) - phenyl, 4-(1,1,2,2 - tetrafluoro-ethoxy) - phenyl, 4-cyclopropyl-phenyl, 4-cyclohexyl-butyl, phenyl, 4-cyclopentyl-phenyl, 4-(2,2-difluoro-cyclopropyl) - phenyl group, 3,4-difluorophenyl, 4-bromo-3-fluorophenyl, 4-bromo-2-fluorophenyl, 4-bromo-2,5-difluorophenyl, 2-fluoro- isopropyl-phenyl, 3-fluoro-4-isopropyl-phenyl, 4-(1-hydroxy-1-methylethyl) - phenyl, 4-(2-hydroxy-2-methylpropyl) - phenyl, 4-acetyl-phenyl, 4-carboxyphenyl, 4-cyanophenyl, 4-hydroxyphenyl, 4- (O--benzyl) - phenyl, 4-(2-methoxy- ethoxy) - phenyl, 4- (CH <sub TranNum = "838"> 2 </ sub> -N (CH <sub TranNum = "839"> 3 </ sub>) <sub TranNum = "840" > 2 </ sub>) - phenyl, 4- (NH-CO-NH <sub TranNum = "841"> 2 </ sub>) - phenyl, 4-(methylthio) - phenyl, 4 (fluorine-methylthio) - phenyl, 4-(difluoro-methylthio) - phenyl, 4-(trifluoromethylthio) - phenyl, 4-(methylsulfonyl ) - phenyl, 4 - (N- -N- methoxy-methyl - amino) - phenyl, 4-(methoxy-amino) - phenyl, 4-(amino-ethoxy) - phenyl, 4- (N- methyl aminooxy) - phenyl, 4- (N, N- dimethylamino group) - phenyl, 4-(azetidin-l-yl) - phenyl, 4-(2-methyl- azetidin-1-yl) - phenyl, 4 - ((S) -2--methyl-azetidin-1-yl) - phenyl, 4 - ((R) -2- methyl azetidin-1-yl) - phenyl, 4-(3-fluoro-azetidin-1-yl) - phenyl, 4-(3-methoxy-azetidine-1 yl) - phenyl, 4-(3-hydroxy-azetidin-1-yl) - phenyl, 4-(pyrrolidin-1-yl) - phenyl, 4-(pyrrolidin-2-yl) - phenyl, 4 - ((S) - pyrrolidin-2-yl) - phenyl, 4 - ((R) - pyrrolidin-2-yl) - phenyl, 4-(pyrrolidin-3-yl) - phenyl, 4 - ((S) - pyrrolidin-3-yl) - phenyl, 4 - ((R) - pyrrolidin-3-yl) - phenyl, 4-(2-fluoro-pyrrolidine -1 - yl) - phenyl, 4 - ((S) -2--fluoro-pyrrolidin-1-yl) - phenyl, 4 - ((R) -2--fluoro-pyrrolidin-1-yl) - phenyl, 4 - (3-fluoro-pyrrolidin-1-yl) - phenyl, 4 - ((S) -3--fluoro-pyrrolidin-1-yl) - phenyl, 4 - ((R) -3- fluoro-pyrrolidine - -1-yl) - phenyl, 4-(2,2-difluoro-pyrrolidin-1-yl) - phenyl, 4-(3,3-difluoro-pyrrolidin-1-yl) - phenyl, 4- (2-methyl-pyrrolidin-1-yl) - phenyl, 4 - ((S) -2--methyl-pyrrolidin-1-yl) - phenyl, 4 - ((R) -2- methylpyrrole 1-yl) - phenyl, 4-(3-methyl-pyrrolidin-1-yl) - phenyl, 4 - ((S) -3--methyl-pyrrolidin-1-yl) - phenyl, 4 - ((R) -3--methyl-pyrrolidin-1-yl) - phenyl, 4-(1-methyl-pyrrolidin-2-yl) - phenyl, 4 - ((S) -1- A pyrrolidin-2-yl) - phenyl, 4 - ((R) -1--methyl-pyrrolidin-2-yl) - phenyl, 4-(1-methyl-pyrrolidin-3-yl) - phenyl yl, 4 - ((S) -1- methyl-pyrrolidin-3-yl) - phenyl, 4 - ((R) -1--methyl-pyrrolidin-3-yl) - phenyl, 4-(2 , 2-methyl-pyrrolidin-1-yl) - phenyl, 4-(3,3-dimethyl-pyrrolidin-1-yl) - phenyl, 4-(2-trifluoromethyl-pyrrolidin - -1-yl) - phenyl, 4 - ((S) -2- trifluoromethyl-pyrrolidin-1-yl) - phenyl, 4 - ((R) -2- trifluoromethyl-pyrrolidin-1- yl) - phenyl, 4-(3-trifluoromethyl-pyrrolidin-1-yl) - phenyl, 4 - ((S) -3- trifluoromethyl-pyrrolidin-1-yl) - phenyl, 4 - ((R) -3- trifluoromethyl-pyrrolidin-1-yl) - phenyl, 4-(2-oxo-pyrrolidin-1-yl) - phenyl, 4-(2-oxo - oxazolidin-3-yl) - phenyl, 4-(piperidin-1-yl) - phenyl, 4-(2-methyl-piperidin-1-yl) - phenyl, 4 - ((S) 2-methyl-piperidin-1-yl) - phenyl, 4 - ((R) -2- methyl-piperidin-1-yl) - phenyl, 4-(piperazin-1-yl) - phenyl group, 4-(4-methyl-piperazin-1-yl) - phenyl, 4-(morpholine-4-yl) - phenyl, 4-(thiomorpholin-4-yl) - phenyl, 4- (1-oxo - thiomorpholin-4-yl) - phenyl, 4-(1,1-dioxo - thiomorpholin-4-yl) - phenyl, 4-(pyrrolidin - -1-yl) - phenyl, 4-(pyrrol-2-yl) - phenyl, 4-(pyrrol-3-yl) - phenyl, 4-(1-methyl-pyrrol-2-yl) - phenyl , 4 (1-methyl-pyrrol-3-yl) - phenyl, 4-(furan-2-yl) - phenyl, 4-(furan-3-yl) - phenyl, 4-(thiophen - 2 - yl) - phenyl, 4-(thiophen-3-yl) - phenyl, 4-(5-propyl-thiophen-2-yl) - phenyl, 4 (pyrazol-1-yl) - phenyl , 4 (pyrazol-3-yl) - phenyl, 4 (pyrazol-4-yl) - phenyl, 4-(1-methyl-pyrazol-4-yl -1H-) - phenyl, 4- (-1H- pyrazol-1-ethyl-4-yl) - phenyl, 4-(1-methyl--1H- pyrazol-5-yl) - phenyl, 4- (1H- imidazole 2-yl) - phenyl, 4-(imidazol-1-yl) - phenyl, 4-(1-methyl-imidazol-2-yl) - phenyl, 4-(-2-yl) - phenyl, 4-(4-yl) - phenyl, 4-(oxazol-5-yl) - phenyl, 4-(isoxazol-3-yl) - phenyl, 4-(iso- 4-yl) - phenyl, 4-(isoxazol-5-yl) - phenyl, 4 - ([1,2,3] - triazol-1-yl) - phenyl, 4- ([1,2,4] - triazol-1-yl) - phenyl, 4 - ([1,2,3] - triazol-2-yl) - phenyl, 4- (4H- [1, 2,4] - triazol-3-yl) - phenyl, 4 - ([1,2,4] - triazol-4-yl) - phenyl, 4- (2H- [1,2,3] - triazol-4-yl) - phenyl, 4-(4-methyl--4H- [1,2,4] - triazol-3-yl) - phenyl, 4-(2-methyl -2H - [1,2,3] - triazol-4-yl) - phenyl, 4 - ([1,3,4] - oxadiazol-2-yl) - phenyl, 4 - ([1,2 , 4] - oxadiazol-3-yl) - phenyl, 4 - ([1,2,4] - oxadiazol-5-yl) - phenyl, 4 - ([1,2,3] - oxadiazol-4-yl) - phenyl, 4 - ([1,2,3] - oxadiazol-5-yl) - phenyl, 4 - ([1,2,3] - thiadiazole - -4-yl) - phenyl, 4- (1H--tetrazol-5-yl) - phenyl, 4-(tetrazol-1-yl) - phenyl, 4-(2-methyl-tetrazole -2H- 5-yl) - phenyl, 4-(1-methyl--1H- tetrazol-5-yl) - phenyl, 4-furazan-3-- phenyl, 4-(pyridin-2-yl ) - phenyl, 4-(pyridin-3-yl) - phenyl, 4-(pyridin-4-yl) - phenyl, 4-(pyrimidin-2-yl) - phenyl, 4-(pyrimidin-4 - yl) - phenyl, 4-(pyrimidin-5-yl) - phenyl, 5-isopropyl-2-phenyl sulfide, 2-chloro-thiazol-5-yl, 2,5-dichloro-thiophene -4 - group, 2,3-dichloro-5-yl, 2-chloro-3-nitro-5-yl, 2-(phenylsulfonyl) - thiophen-5-yl, 2-(pyridin-2 - yl) thiophene-5-yl, 2-(5 - (trifluoromethyl)-3-yl) - thiazol-5-yl, 2-(2-methyl-thiazol-4-yl) - thiophene 5-yl, 1-methyl--1H- imidazol-4-yl, 1,2-dimethyl--1H- imidazol-4-yl, 3,5-dimethyl-4-yl, thiazol- 2-yl, 4-methyl-thiazol-2-yl, 4-isopropyl-thiazol-2-yl, 4-trifluoromethyl-thiazol-2-yl, 5-methyl-thiazol-2-yl, 5 isopropyl-thiazol-2-yl, 5-trifluoromethyl-thiazol-2-yl, 2,4-dimethyl-thiazol-5-yl, 2-acetamido-4-methyl-thiazol-5-yl, 4H - [1,2,4] triazol-3-yl, 5-methyl -4H- [1,2,4] triazol-3-yl, 4-methyl--4H- [1,2,4] triazol-3-yl, 5-isopropyl--4H- [1,2,4] triazol-3-yl, 5-trifluoromethyl -4H- [1,2,4] triazol-3- group, a 4,5-dimethyl -4H- [1,2,4] triazol-3-yl, 5-isopropyl-4-methyl -4H- [1,2,4] triazol - group, 5-trifluoromethyl-4-methyl -4H- [1,2,4] triazol-3-yl, [1,3,4] thiadiazol-2-yl, 5-methyl- - [1,3,4] thiadiazol-2-yl, 5-isopropyl-- [1,3,4] thiadiazol-2-yl, 5-trifluoromethyl - [1,3,4 ] thiadiazol-2-yl, 3-bromo-2-chloro-pyridin-5-yl, 2-(4-morpholino) - pyridin-5-yl, 2-phenoxy-5-yl, ( 2-isopropyl-yl) - pyrimidin-5-yl, (5-isopropyl-yl) - pyrimidin-2-yl, 8-quinolyl, 5-isoquinolyl, 2-(trifluoroacetyl) -1 1,2,3,4-tetrahydro-isoquinoline-7-yl, 5-chloro-3-methyl-benzothiophene-2-yl, 3,4-dihydro-4-methyl -2H--benzo [ b] [1,4] oxazine-yl, benzothiazol-6-yl, benzo [2,1,3] oxadiazole-4-yl, 5-chlorobenzo [2,1,3] oxadiazole -4-yl, 7-chlorobenzo [2,1,3] oxadiazol-4-yl and benzo [2,1,3] thiadiazol-4-yl.
Particularly preferred Compound I is formula I.a, I.b, I.c, I.d, I.e, I.f, I.g, I.h, I.i, I.k, I.l, I.m, I.n, I.o, I.p, I.q, I.r, I.s and I.t compound, wherein R 1there is implication defined above with Ar.R 1with the preferred meaning of Ar as defined above.
The example of the compound of preferred formula I.a, I.b, I.c, I.d, I.e, I.f, I.g, I.h, I.i, I.k, I.l, I.m, I.n, I.o, I.p, I.q, I.r, I.s and I.t representative is individually oriented compound listed above, wherein variables A r and R 1there is given implication in a row of Table A.
Table A
Numbering R 1 Ar
1 Propyl group 4-aminomethyl phenyl
2 Propyl group 4-ethylphenyl
3 Propyl group 4-propyl group phenyl
4 Propyl group 4-isopropyl phenyl
5 Propyl group 4-secondary butyl phenenyl
6 Propyl group 4-isobutyl phenenyl
7 Propyl group 4-(1,1-dimethyl propyl)-phenyl
8 Propyl group 4-ethenylphenyl
9 Propyl group 4-pseudoallyl phenyl
10 Propyl group 4-fluorophenyl
11 Propyl group 4-chloro-phenyl-
12 Propyl group 4-bromophenyl
13 Propyl group 4-(methyl fluoride) phenyl
14 Propyl group 3-(methyl fluoride) phenyl
15 Propyl group 2-(methyl fluoride) phenyl
16 Propyl group 4-(difluoromethyl) phenyl
17 Propyl group 3-(difluoromethyl) phenyl
18 Propyl group 2-(difluoromethyl) phenyl
19 Propyl group 4-(trifluoromethyl) phenyl
20 Propyl group 3-(trifluoromethyl) phenyl
21 Propyl group 2-(trifluoromethyl) phenyl
22 Propyl group 4-(1-fluoro ethyl)-phenyl
23 Propyl group 4-((S)-1-fluoro ethyl)-phenyl
24 Propyl group 4-((R)-1-fluoro ethyl)-phenyl
25 Propyl group 4-(2-fluoro ethyl)-phenyl
26 Propyl group 4-(1,1-, bis-fluoro ethyls)-phenyl
27 Propyl group 4-(2,2-, bis-fluoro ethyls)-phenyl
Numbering R 1 Ar
28 Propyl group 4-(2,2,2-trifluoroethyl)-phenyl
29 Propyl group 4-(3-fluoropropyl)-phenyl
30 Propyl group 4-(2-fluoropropyl)-phenyl
31 Propyl group 4-((S)-2-fluoropropyl)-phenyl
32 Propyl group 4-((R)-2-fluoropropyl)-phenyl
33 Propyl group 4-(3,3-, bis-fluoropropyls)-phenyl
34 Propyl group 4-(3,3,3-trifluoro propyl)-phenyl
35 Propyl group 4-(the fluoro-1-methylethyl of 1-)-phenyl
36 Propyl group 4-(the fluoro-1-methylethyl of 2-)-phenyl
37 Propyl group 4-(the fluoro-1-methylethyl of (S)-2-)-phenyl
38 Propyl group 4-(the fluoro-1-methylethyl of (R)-2-)-phenyl
39 Propyl group 4-(the fluoro-1-methylethyl of 2,2-bis-)-phenyl
40 Propyl group 4-((S)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
41 Propyl group 4-((R)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
42 Propyl group 4-(the fluoro-1-methylethyl of 2,2,2-tri-)-phenyl
43 Propyl group 4-((S)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
44 Propyl group 4-((R)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
45 Propyl group 4-(the fluoro-1-methyl fluoride of 2-ethyl)-phenyl
46 Propyl group 4-(1-difluoromethyl-2,2-bis-fluoro ethyls)-phenyl
47 Propyl group 4-(1,1-dimethyl-2-fluoro ethyl)-phenyl
48 Propyl group 4-p-methoxy-phenyl
49 Propyl group 4-ethoxyl phenenyl
50 Propyl group 4-propoxy-phenyl
51 Propyl group 4-isopropyl phenyl
52 Propyl group 4-butoxy phenyl
53 Propyl group 4-(fluorine methoxyl group)-phenyl
54 Propyl group 4-(difluoro-methoxy)-phenyl
55 Propyl group 4-(trifluoromethoxy)-phenyl
56 Propyl group 3-(trifluoromethoxy)-phenyl
57 Propyl group 4-(2-fluorine oxyethyl group)-phenyl
Numbering R 1 Ar
58 Propyl group 4-(2,2-difluoroethoxy)-phenyl
59 Propyl group 4-(2,2,2-trifluoro ethoxy)-phenyl
60 Propyl group 4-(1,1,2,2-tetrafluoro oxyethyl group)-phenyl
61 Propyl group 4-cyclopropyl phenyl
62 Propyl group 4-cyclobutyl phenyl
63 Propyl group 4-cyclopentyl phenyl
64 Propyl group 4-(2,2-difluoro cyclopropyl)-phenyl
65 Propyl group 3,4-difluorophenyl
66 Propyl group 4-bromine-3-fluorophenyl
67 Propyl group The bromo-2-fluorophenyl of 4-
68 Propyl group 4-is bromo-2,5-difluorophenyl
69 Propyl group The fluoro-4-isopropyl phenyl of 2-
70 Propyl group The fluoro-4-isopropyl phenyl of 3-
71 Propyl group 4-(1-hydroxyl-1-methylethyl)-phenyl
72 Propyl group 4-(2-hydroxy-2-methyl propyl group)-phenyl
73 Propyl group 4-acetylphenyl
74 Propyl group 4-carboxyl phenyl
75 Propyl group 4-cyano-phenyl
76 Propyl group 4-hydroxy phenyl
77 Propyl group 4-(O-benzyl)-phenyl
78 Propyl group 4-(2-methoxy ethoxy)-phenyl
79 Propyl group 4-(CH 2-N(CH 3) 2)-phenyl
80 Propyl group 4-(NH-CO-NH 2)-phenyl
81 Propyl group 4-(methylthio group)-phenyl
82 Propyl group 4-(fluorine methylthio group)-phenyl
83 Propyl group 4-(difluoro methylthio group)-phenyl
84 Propyl group 4-(trifluoromethylthio)-phenyl
85 Propyl group 4-(methyl sulphonyl)-phenyl
86 Propyl group 4-(N-methoxyl group-N-methyl-amino)-phenyl
87 Propyl group 4-(methoxyl group is amino)-phenyl
Numbering R 1 Ar
88 Propyl group 4-(oxyethyl group is amino)-phenyl
89 Propyl group 4-(N-methylamino oxygen base)-phenyl
90 Propyl group 4-(N, N-dimethylamino oxygen base)-phenyl
91 Propyl group 4-(azetidine-1-yl)-phenyl
92 Propyl group 4-(2-methyl azetidine-1-yl)-phenyl
93 Propyl group 4-((S)-2-methyl azetidine-1-yl)-phenyl
94 Propyl group 4-((R)-2-methyl azetidine-1-yl)-phenyl
95 Propyl group 4-(3-fluorine azetidine-1-yl)-phenyl
96 Propyl group 4-(3-methoxyl group azetidine-1-yl)-phenyl
97 Propyl group 4-(3-hydroxy azetidine-1-yl)-phenyl
98 Propyl group 4-(pyrrolidin-1-yl)-phenyl
99 Propyl group 4-(pyrrolidin-2-yl)-phenyl
100 Propyl group 4-((S)-pyrrolidin-2-yl)-phenyl
101 Propyl group 4-((R)-pyrrolidin-2-yl)-phenyl
102 Propyl group 4-(pyrrolidin-3-yl)-phenyl
103 Propyl group 4-((S)-pyrrolidin-3-yl)-phenyl
104 Propyl group 4-((R)-pyrrolidin-3-yl)-phenyl
105 Propyl group 4-(2-fluoropyrrolidine-1-yl)-phenyl
106 Propyl group 4-((S)-2-fluoropyrrolidine-1-yl)-phenyl
107 Propyl group 4-((R)-2-fluoropyrrolidine-1-yl)-phenyl
108 Propyl group 4-(3-fluoropyrrolidine-1-yl)-phenyl
109 Propyl group 4-((S)-3-fluoropyrrolidine-1-yl)-phenyl
110 Propyl group 4-((R)-3-fluoropyrrolidine-1-yl)-phenyl
111 Propyl group 4-(2,2-difluoro pyrrolidin-1-yl)-phenyl
112 Propyl group 4-(3,3-difluoro pyrrolidin-1-yl)-phenyl
113 Propyl group 4-(2-methylpyrrolidin-1-yl)-phenyl
114 Propyl group 4-((S)-2-methylpyrrolidin-1-yl)-phenyl
115 Propyl group 4-((R)-2-methylpyrrolidin-1-yl)-phenyl
116 Propyl group 4-(3-methylpyrrolidin-1-yl)-phenyl
117 Propyl group 4-((S)-3-methylpyrrolidin-1-yl)-phenyl
Numbering R 1 Ar
118 Propyl group 4-((R)-3-methylpyrrolidin-1-yl)-phenyl
119 Propyl group 4-(1-methylpyrrolidin-2-yl)-phenyl
120 Propyl group 4-((S)-1-methylpyrrolidin-2-yl)-phenyl
121 Propyl group 4-((R)-1-methylpyrrolidin-2-yl)-phenyl
122 Propyl group 4-(1-methylpyrrolidin-3-yl)-phenyl
123 Propyl group 4-((S)-1-methylpyrrolidin-3-yl)-phenyl
124 Propyl group 4-((R)-1-methylpyrrolidin-3-yl)-phenyl
125 Propyl group 4-(2,2-dimethyl pyrrolidine-1-yl)-phenyl
126 Propyl group 4-(3,3-dimethyl pyrrolidine-1-yl)-phenyl
127 Propyl group 4-(2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
128 Propyl group 4-((S)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
129 Propyl group 4-((R)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
130 Propyl group 4-(3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
131 Propyl group 4-((S)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
132 Propyl group 4-((R)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
133 Propyl group 4-(2-oxo-pyrrolidine-1-yl)-phenyl
134 Propyl group 4-(2-oxo-oxazolidines-3-yl)-phenyl
135 Propyl group 4-(piperidin-1-yl)-phenyl
136 Propyl group 4-(pipecoline-1-yl)-phenyl
137 Propyl group 4-((S)-pipecoline-1-yl)-phenyl
138 Propyl group 4-((R)-pipecoline-1-yl)-phenyl
139 Propyl group 4-(piperazine-1-yl)-phenyl
140 Propyl group 4-(4-methylpiperazine-1-yl)-phenyl
141 Propyl group 4-(morpholine-4-yl)-phenyl
142 Propyl group 4-(thiomorpholine-4-yl)-phenyl
143 Propyl group 4-(1-oxo-thiomorpholine-4-yl)-phenyl
144 Propyl group 4-(1,1-dioxo-thiomorpholine-4-yl)-phenyl
145 Propyl group 4-(pyrroles-1-yl)-phenyl
146 Propyl group 4-(pyrroles-2-yl)-phenyl
147 Propyl group 4-(pyrroles-3-yl)-phenyl
Numbering R 1 Ar
148 Propyl group 4-(1-methylpyrrole-2-yl)-phenyl
149 Propyl group 4-(1-methylpyrrole-3-yl)-phenyl
150 Propyl group 4-(furans-2-yl)-phenyl
151 Propyl group 4-(furans-3-yl)-phenyl
152 Propyl group 4-(thiophene-2-yl)-phenyl
153 Propyl group 4-(thiene-3-yl-)-phenyl
154 Propyl group 4-(5-propyl group thiophene-2-yl)-phenyl
155 Propyl group 4-(pyrazol-1-yl)-phenyl
156 Propyl group 4-(pyrazole-3-yl)-phenyl
157 Propyl group 4-(pyrazoles-4-yl)-phenyl
158 Propyl group 4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl
159 Propyl group 4-(1-ethyl-1H-pyrazoles-4-yl)-phenyl
160 Propyl group 4-(1-methyl isophthalic acid H-pyrazoles-5-yl)-phenyl
161 Propyl group 4-(1H-imidazoles-2-yl)-phenyl
162 Propyl group 4-(imidazoles-1-yl)-phenyl
163 Propyl group 4-(1-Methylimidazole-2-yl)-phenyl
164 Propyl group 4-(oxazole-2-yl)-phenyl
165 Propyl group 4-(oxazole-4-yl)-phenyl
166 Propyl group 4-(oxazole-5-yl)-phenyl
167 Propyl group 4-(isoxazole-3-base)-phenyl
168 Propyl group 4-(isoxazole-4-base)-phenyl
169 Propyl group 4-(isoxazole-5-base)-phenyl
170 Propyl group 4-([1,2,3]-triazol-1-yl)-phenyl
171 Propyl group 4-([1,2,4]-triazol-1-yl)-phenyl
172 Propyl group 4-([1,2,3]-triazole-2-yl)-phenyl
173 Propyl group 4-(4H-[1,2,4]-triazole-3-yl)-phenyl
174 Propyl group 4-([1,2,4]-triazole-4-yl)-phenyl
175 Propyl group 4-(2H-[1,2,3]-triazole-4-yl)-phenyl
176 Propyl group 4-(4-methyl-4H-[1,2,4]-triazole-3-yl)-phenyl
177 Propyl group 4-(2-methyl-2H-[1,2,3]-triazole-4-yl)-phenyl
Numbering R 1 Ar
178 Propyl group 4-([1,3,4]-oxadiazoles-2-yl)-phenyl
179 Propyl group 4-([1,2,4]-oxadiazoles-3-yl)-phenyl
180 Propyl group 4-([1,2,4]-oxadiazoles-5-yl)-phenyl
181 Propyl group 4-([1,2,3]-oxadiazoles-4-yl)-phenyl
182 Propyl group 4-([1,2,3]-oxadiazoles-5-yl)-phenyl
183 Propyl group 4-([1,2,3]-thiadiazoles-4-yl)-phenyl
184 Propyl group 4-(1H-TETRAZOLE-5-yl)-phenyl
185 Propyl group 4-(tetrazolium-1-yl)-phenyl
186 Propyl group 4-(2-methyl-2H-tetrazolium-5-yl)-phenyl
187 Propyl group 4-(1-methyl isophthalic acid H-tetrazolium-5-yl)-phenyl
188 Propyl group 4-furazan-3-base-phenyl
189 Propyl group 4-(pyridine-2-yl)-phenyl
190 Propyl group 4-(pyridin-3-yl)-phenyl
191 Propyl group 4-(pyridin-4-yl)-phenyl
192 Propyl group 4-(pyrimidine-2-base)-phenyl
193 Propyl group 4-(pyrimidine-4-yl)-phenyl
194 Propyl group 4-(pyrimidine-5-yl)-phenyl
195 Propyl group 5-isopropyl sulfenyl benzene-2-base
196 Propyl group 2-chlorothiophene-5-base
197 Propyl group 2,5-dichloro-thiophene-4-base
198 Propyl group 2,3-dichloro-thiophene-5-base
199 Propyl group The chloro-3-nitrothiophene-5-of 2-base
200 Propyl group 2-(phenyl sulfonyl)-thiophene-5-base
201 Propyl group 2-(pyridine-2-yl) thiophene-5-base
202 Propyl group 2-(5-(trifluoromethyl) isoxazole-3-base)-thiophene-5-base
203 Propyl group 2-(2-methylthiazol-4-yl)-thiophene-5-base
204 Propyl group 1-methyl isophthalic acid H-imidazol-4 yl
205 Propyl group 1,2-dimethyl-1H-imidazol-4 yl
206 Propyl group 3,5-dimethyl isoxazole-4-base
207 Propyl group Thiazol-2-yl
Numbering R 1 Ar
208 Propyl group 4-methylthiazol-2-base
209 Propyl group 4-sec.-propyl thiazol-2-yl
210 Propyl group 4-trifluoromethyl thiazole-2-base
211 Propyl group 5-methylthiazol-2-base
212 Propyl group 5-sec.-propyl thiazol-2-yl
213 Propyl group 5-trifluoromethyl thiazole-2-base
214 Propyl group 2,4-dimethylthiazole-5-base
215 Propyl group 2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-base
216 Propyl group 4H-[1,2,4] triazole-3-base
217 Propyl group 5-methyl-4H-[1,2,4] triazole-3-base
218 Propyl group 4-methyl-4H-[1,2,4] triazole-3-base
219 Propyl group 5-sec.-propyl-4H-[1,2,4] triazole-3-base
220 Propyl group 5-trifluoromethyl-4H-[1,2,4] triazole-3-base
221 Propyl group 4,5-dimethyl-4H-[1,2,4] triazole-3-base
222 Propyl group 5-isopropyl-4-methyl-4H-[1,2,4] triazole-3-base
223 Propyl group 5-trifluoromethyl-4-methyl-4H-[1,2,4] triazole-3-base
224 Propyl group [1,3,4] thiadiazoles-2-base
225 Propyl group 5-methyl-[1,3,4] thiadiazoles-2-base
226 Propyl group 5-sec.-propyl-[1,3,4] thiadiazoles-2-base
227 Propyl group 5-trifluoromethyl-[1,3,4] thiadiazoles-2-base
228 Propyl group The bromo-2-chloropyridine-5-of 3-base
229 Propyl group 2-(4-morpholino)-pyridine-5-base
230 Propyl group 2-phenoxypyridines-5-base
231 Propyl group (2-sec.-propyl)-pyrimidine-5-base
232 Propyl group (5-sec.-propyl)-pyrimidine-2-base
233 Propyl group 8-quinolyl
234 Propyl group 5-isoquinolyl
235 Propyl group 2-(trifluoroacetyl group)-1,2,3,4-tetrahydroisoquinoline-7-base
236 Propyl group The chloro-3-methylbenzene thiophthene-2-of 5-base
237 Propyl group 3,4-dihydro-4-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazinyl
Numbering R 1 Ar
238 Propyl group Benzothiazol-6-yl
239 Propyl group Benzo [2,1,3] oxadiazole-4-bases
240 Propyl group 5-chlorobenzene is [2,1,3] oxadiazole-4-bases also
241 Propyl group 7-chlorobenzene is [2,1,3] oxadiazole-4-bases also
242 Propyl group Benzo [2,1,3] thiadiazoles-4-base
243 Ethyl 4-aminomethyl phenyl
244 Ethyl 4-ethylphenyl
245 Ethyl 4-propyl group phenyl
246 Ethyl 4-isopropyl phenyl
247 Ethyl 4-secondary butyl phenenyl
248 Ethyl 4-isobutyl phenenyl
249 Ethyl 4-(1,1-dimethyl propyl)-phenyl
250 Ethyl 4-ethenylphenyl
251 Ethyl 4-pseudoallyl phenyl
252 Ethyl 4-fluorophenyl
253 Ethyl 4-chloro-phenyl-
254 Ethyl 4-bromophenyl
255 Ethyl 4-(methyl fluoride) phenyl
256 Ethyl 3-(methyl fluoride) phenyl
257 Ethyl 2-(methyl fluoride) phenyl
258 Ethyl 4-(difluoromethyl) phenyl
259 Ethyl 3-(difluoromethyl) phenyl
260 Ethyl 2-(difluoromethyl) phenyl
261 Ethyl 4-(trifluoromethyl) phenyl
262 Ethyl 3-(trifluoromethyl) phenyl
263 Ethyl 2-(trifluoromethyl) phenyl
264 Ethyl 4-(1-fluoro ethyl)-phenyl
265 Ethyl 4-((S)-1-fluoro ethyl)-phenyl
266 Ethyl 4-((R)-1-fluoro ethyl)-phenyl
267 Ethyl 4-(2-fluoro ethyl)-phenyl
Numbering R 1 Ar
268 Ethyl 4-(1,1-, bis-fluoro ethyls)-phenyl
269 Ethyl 4-(2,2-, bis-fluoro ethyls)-phenyl
270 Ethyl 4-(2,2,2-trifluoroethyl)-phenyl
271 Ethyl 4-(3-fluoropropyl)-phenyl
272 Ethyl 4-(2-fluoropropyl)-phenyl
273 Ethyl 4-((S)-2-fluoropropyl)-phenyl
274 Ethyl 4-((R)-2-fluoropropyl)-phenyl
275 Ethyl 4-(3,3-, bis-fluoropropyls)-phenyl
276 Ethyl 4-(3,3,3-trifluoro propyl)-phenyl
277 Ethyl 4-(the fluoro-1-methylethyl of 1-)-phenyl
278 Ethyl 4-(the fluoro-1-methylethyl of 2-)-phenyl
279 Ethyl 4-(the fluoro-1-methylethyl of (S)-2-)-phenyl
280 Ethyl 4-(the fluoro-1-methylethyl of (R)-2-)-phenyl
281 Ethyl 4-(the fluoro-1-methylethyl of 2,2-bis-)-phenyl
282 Ethyl 4-((S)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
283 Ethyl 4-((R)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
284 Ethyl 4-(the fluoro-1-methylethyl of 2,2,2-tri-)-phenyl
285 Ethyl 4-((S)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
286 Ethyl 4-((R)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
287 Ethyl 4-(the fluoro-1-methyl fluoride of 2-ethyl)-phenyl
288 Ethyl 4-(1-difluoromethyl-2,2-bis-fluoro ethyls)-phenyl
289 Ethyl 4-(1,1-dimethyl-2-fluoro ethyl)-phenyl
290 Ethyl 4-p-methoxy-phenyl
291 Ethyl 4-ethoxyl phenenyl
292 Ethyl 4-propoxy-phenyl
293 Ethyl 4-isopropyl phenyl
294 Ethyl 4-butoxy phenyl
295 Ethyl 4-(fluorine methoxyl group)-phenyl
296 Ethyl 4-(difluoro-methoxy)-phenyl
297 Ethyl 4-(trifluoromethoxy)-phenyl
Numbering R 1 Ar
298 Ethyl 3-(trifluoromethoxy)-phenyl
299 Ethyl 4-(2-fluorine oxyethyl group)-phenyl
300 Ethyl 4-(2,2-difluoroethoxy)-phenyl
301 Ethyl 4-(2,2,2-trifluoro ethoxy)-phenyl
302 Ethyl 4-(1,1,2,2-tetrafluoro oxyethyl group)-phenyl
303 Ethyl 4-cyclopropyl phenyl
304 Ethyl 4-cyclobutyl phenyl
305 Ethyl 4-cyclopentyl phenyl
306 Ethyl 4-(2,2-difluoro cyclopropyl)-phenyl
307 Ethyl 3,4-difluorophenyl
308 Ethyl 4-bromine-3-fluorophenyl
309 Ethyl The bromo-2-fluorophenyl of 4-
310 Ethyl 4-is bromo-2,5-difluorophenyl
311 Ethyl The fluoro-4-isopropyl phenyl of 2-
312 Ethyl The fluoro-4-isopropyl phenyl of 3-
313 Ethyl 4-(1-hydroxyl-1-methylethyl)-phenyl
314 Ethyl 4-(2-hydroxy-2-methyl propyl group)-phenyl
315 Ethyl 4-acetylphenyl
316 Ethyl 4-carboxyl phenyl
317 Ethyl 4-cyano-phenyl
318 Ethyl 4-hydroxy phenyl
319 Ethyl 4-(O-benzyl)-phenyl
320 Ethyl 4-(2-methoxy ethoxy)-phenyl
321 Ethyl 4-(CH 2-N(CH 3) 2)-phenyl
322 Ethyl 4-(NH-CO-NH 2)-phenyl
323 Ethyl 4-(methylthio group)-phenyl
324 Ethyl 4-(fluorine methylthio group)-phenyl
325 Ethyl 4-(difluoro methylthio group)-phenyl
326 Ethyl 4-(trifluoromethylthio)-phenyl
327 Ethyl 4-(methyl sulphonyl)-phenyl
Numbering R 1 Ar
328 Ethyl 4-(N-methoxyl group-N-methyl-amino)-phenyl
329 Ethyl 4-(methoxyl group is amino)-phenyl
330 Ethyl 4-(oxyethyl group is amino)-phenyl
331 Ethyl 4-(N-methylamino oxygen base)-phenyl
332 Ethyl 4-(N, N-dimethylamino oxygen base)-phenyl
333 Ethyl 4-(azetidine-1-yl)-phenyl
334 Ethyl 4-(2-methyl azetidine-1-yl)-phenyl
335 Ethyl 4-((S)-2-methyl azetidine-1-yl)-phenyl
336 Ethyl 4-((R)-2-methyl azetidine-1-yl)-phenyl
337 Ethyl 4-(3-fluorine azetidine-1-yl)-phenyl
338 Ethyl 4-(3-methoxyl group azetidine-1-yl)-phenyl
339 Ethyl 4-(3-hydroxy azetidine-1-yl)-phenyl
340 Ethyl 4-(pyrrolidin-1-yl)-phenyl
341 Ethyl 4-(pyrrolidin-2-yl)-phenyl
342 Ethyl 4-((S)-pyrrolidin-2-yl)-phenyl
343 Ethyl 4-((R)-pyrrolidin-2-yl)-phenyl
344 Ethyl 4-(pyrrolidin-3-yl)-phenyl
345 Ethyl 4-((S)-pyrrolidin-3-yl)-phenyl
346 Ethyl 4-((R)-pyrrolidin-3-yl)-phenyl
347 Ethyl 4-(2-fluoropyrrolidine-1-yl)-phenyl
348 Ethyl 4-((S)-2-fluoropyrrolidine-1-yl)-phenyl
349 Ethyl 4-((R)-2-fluoropyrrolidine-1-yl)-phenyl
350 Ethyl 4-(3-fluoropyrrolidine-1-yl)-phenyl
351 Ethyl 4-((S)-3-fluoropyrrolidine-1-yl)-phenyl
352 Ethyl 4-((R)-3-fluoropyrrolidine-1-yl)-phenyl
353 Ethyl 4-(2,2-difluoro pyrrolidin-1-yl)-phenyl
354 Ethyl 4-(3,3-difluoro pyrrolidin-1-yl)-phenyl
355 Ethyl 4-(2-methylpyrrolidin-1-yl)-phenyl
356 Ethyl 4-((S)-2-methylpyrrolidin-1-yl)-phenyl
357 Ethyl 4-((R)-2-methylpyrrolidin-1-yl)-phenyl
Numbering R 1 Ar
358 Ethyl 4-(3-methylpyrrolidin-1-yl)-phenyl
359 Ethyl 4-((S)-3-methylpyrrolidin-1-yl)-phenyl
360 Ethyl 4-((R)-3-methylpyrrolidin-1-yl)-phenyl
361 Ethyl 4-(1-methylpyrrolidin-2-yl)-phenyl
362 Ethyl 4-((S)-1-methylpyrrolidin-2-yl)-phenyl
363 Ethyl 4-((R)-1-methylpyrrolidin-2-yl)-phenyl
364 Ethyl 4-(1-methylpyrrolidin-3-yl)-phenyl
365 Ethyl 4-((S)-1-methylpyrrolidin-3-yl)-phenyl
366 Ethyl 4-((R)-1-methylpyrrolidin-3-yl)-phenyl
367 Ethyl 4-(2,2-dimethyl pyrrolidine-1-yl)-phenyl
368 Ethyl 4-(3,3-dimethyl pyrrolidine-1-yl)-phenyl
369 Ethyl 4-(2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
370 Ethyl 4-((S)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
371 Ethyl 4-((R)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
372 Ethyl 4-(3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
373 Ethyl 4-((S)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
374 Ethyl 4-((R)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
375 Ethyl 4-(2-oxo-pyrrolidine-1-yl)-phenyl
376 Ethyl 4-(2-oxo-oxazolidines-3-yl)-phenyl
377 Ethyl 4-(piperidin-1-yl)-phenyl
378 Ethyl 4-(pipecoline-1-yl)-phenyl
379 Ethyl 4-((S)-pipecoline-1-yl)-phenyl
380 Ethyl 4-((R)-pipecoline-1-yl)-phenyl
381 Ethyl 4-(piperazine-1-yl)-phenyl
382 Ethyl 4-(4-methylpiperazine-1-yl)-phenyl
383 Ethyl 4-(morpholine-4-yl)-phenyl
384 Ethyl 4-(thiomorpholine-4-yl)-phenyl
385 Ethyl 4-(1-oxo-thiomorpholine-4-yl)-phenyl
386 Ethyl 4-(1,1-dioxo-thiomorpholine-4-yl)-phenyl
387 Ethyl 4-(pyrroles-1-yl)-phenyl
Numbering R 1 Ar
388 Ethyl 4-(pyrroles-2-yl)-phenyl
389 Ethyl 4-(pyrroles-3-yl)-phenyl
390 Ethyl 4-(1-methylpyrrole-2-yl)-phenyl
391 Ethyl 4-(1-methylpyrrole-3-yl)-phenyl
392 Ethyl 4-(furans-2-yl)-phenyl
393 Ethyl 4-(furans-3-yl)-phenyl
394 Ethyl 4-(thiophene-2-yl)-phenyl
395 Ethyl 4-(thiene-3-yl-)-phenyl
396 Ethyl 4-(5-propyl group thiophene-2-yl)-phenyl
397 Ethyl 4-(pyrazol-1-yl)-phenyl
398 Ethyl 4-(pyrazole-3-yl)-phenyl
399 Ethyl 4-(pyrazoles-4-yl)-phenyl
400 Ethyl 4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl
401 Ethyl 4-(1-ethyl-1H-pyrazoles-4-yl)-phenyl
402 Ethyl 4-(1-methyl isophthalic acid H-pyrazoles-5-yl)-phenyl
403 Ethyl 4-(1H-imidazoles-2-yl)-phenyl
404 Ethyl 4-(imidazoles-1-yl)-phenyl
405 Ethyl 4-(1-Methylimidazole-2-yl)-phenyl
406 Ethyl 4-(oxazole-2-yl)-phenyl
407 Ethyl 4-(oxazole-4-yl)-phenyl
408 Ethyl 4-(oxazole-5-yl)-phenyl
409 Ethyl 4-(isoxazole-3-base)-phenyl
410 Ethyl 4-(isoxazole-4-base)-phenyl
411 Ethyl 4-(isoxazole-5-base)-phenyl
412 Ethyl 4-([1,2,3]-triazol-1-yl)-phenyl
413 Ethyl 4-([1,2,4]-triazol-1-yl)-phenyl
414 Ethyl 4-([1,2,3]-triazole-2-yl)-phenyl
415 Ethyl 4-(4H-[1,2,4]-triazole-3-yl)-phenyl
416 Ethyl 4-([1,2,4]-triazole-4-yl)-phenyl
417 Ethyl 4-(2H-[1,2,3]-triazole-4-yl)-phenyl
Numbering R 1 Ar
418 Ethyl 4-(4-methyl-4H-[1,2,4]-triazole-3-yl)-phenyl
419 Ethyl 4-(2-methyl-2H-[1,2,3]-triazole-4-yl)-phenyl
420 Ethyl 4-([1,3,4]-oxadiazoles-2-yl)-phenyl
421 Ethyl 4-([1,2,4]-oxadiazoles-3-yl)-phenyl
422 Ethyl 4-([1,2,4]-oxadiazoles-5-yl)-phenyl
423 Ethyl 4-([1,2,3]-oxadiazoles-4-yl)-phenyl
424 Ethyl 4-([1,2,3]-oxadiazoles-5-yl)-phenyl
425 Ethyl 4-([1,2,3]-thiadiazoles-4-yl)-phenyl
426 Ethyl 4-(1H-TETRAZOLE-5-yl)-phenyl
427 Ethyl 4-(tetrazolium-1-yl)-phenyl
428 Ethyl 4-(2-methyl-2H-tetrazolium-5-yl)-phenyl
429 Ethyl 4-(1-methyl isophthalic acid H-tetrazolium-5-yl)-phenyl
430 Ethyl 4-furazan-3-base-phenyl
431 Ethyl 4-(pyridine-2-yl)-phenyl
432 Ethyl 4-(pyridin-3-yl)-phenyl
433 Ethyl 4-(pyridin-4-yl)-phenyl
434 Ethyl 4-(pyrimidine-2-base)-phenyl
435 Ethyl 4-(pyrimidine-4-yl)-phenyl
436 Ethyl 4-(pyrimidine-5-yl)-phenyl
437 Ethyl 5-isopropyl sulfenyl benzene-2-base
438 Ethyl 2-chlorothiophene-5-base
439 Ethyl 2,5-dichloro-thiophene-4-base
440 Ethyl 2,3-dichloro-thiophene-5-base
441 Ethyl The chloro-3-nitrothiophene-5-of 2-base
442 Ethyl 2-(phenyl sulfonyl)-thiophene-5-base
443 Ethyl 2-(pyridine-2-yl) thiophene-5-base
444 Ethyl 2-(5-(trifluoromethyl) isoxazole-3-base)-thiophene-5-base
445 Ethyl 2-(2-methylthiazol-4-yl)-thiophene-5-base
446 Ethyl 1-methyl isophthalic acid H-imidazol-4 yl
447 Ethyl 1,2-dimethyl-1H-imidazol-4 yl
Numbering R 1 Ar
448 Ethyl 3,5-dimethyl isoxazole-4-base
449 Ethyl Thiazol-2-yl
450 Ethyl 4-methylthiazol-2-base
451 Ethyl 4-sec.-propyl thiazol-2-yl
452 Ethyl 4-trifluoromethyl thiazole-2-base
453 Ethyl 5-methylthiazol-2-base
454 Ethyl 5-sec.-propyl thiazol-2-yl
455 Ethyl 5-trifluoromethyl thiazole-2-base
456 Ethyl 2,4-dimethylthiazole-5-base
457 Ethyl 2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-base
458 Ethyl 4H-[1,2,4] triazole-3-base
459 Ethyl 5-methyl-4H-[1,2,4] triazole-3-base
460 Ethyl 4-methyl-4H-[1,2,4] triazole-3-base
461 Ethyl 5-sec.-propyl-4H-[1,2,4] triazole-3-base
462 Ethyl 5-trifluoromethyl-4H-[1,2,4] triazole-3-base
463 Ethyl 4,5-dimethyl-4H-[1,2,4] triazole-3-base
464 Ethyl 5-isopropyl-4-methyl-4H-[1,2,4] triazole-3-base
465 Ethyl 5-trifluoromethyl-4-methyl-4H-[1,2,4] triazole-3-base
466 Ethyl [1,3,4] thiadiazoles-2-base
467 Ethyl 5-methyl-[1,3,4] thiadiazoles-2-base
468 Ethyl 5-sec.-propyl-[1,3,4] thiadiazoles-2-base
469 Ethyl 5-trifluoromethyl-[1,3,4] thiadiazoles-2-base
470 Ethyl The bromo-2-chloropyridine-5-of 3-base
471 Ethyl 2-(4-morpholino)-pyridine-5-base
472 Ethyl 2-phenoxypyridines-5-base
473 Ethyl (2-sec.-propyl)-pyrimidine-5-base
474 Ethyl (5-sec.-propyl)-pyrimidine-2-base
475 Ethyl 8-quinolyl
476 Ethyl 5-isoquinolyl
477 Ethyl 2-(trifluoroacetyl group)-1,2,3,4-tetrahydroisoquinoline-7-base
Numbering R 1 Ar
478 Ethyl The chloro-3-methylbenzene thiophthene-2-of 5-base
479 Ethyl 3,4-dihydro-4-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazinyl
480 Ethyl Benzothiazol-6-yl
481 Ethyl Benzo [2,1,3] oxadiazole-4-bases
482 Ethyl 5-chlorobenzene is [2,1,3] oxadiazole-4-bases also
483 Ethyl 7-chlorobenzene is [2,1,3] oxadiazole-4-bases also
484 Ethyl Benzo [2,1,3] thiadiazoles-4-base
485 Methyl 4-aminomethyl phenyl
486 Methyl 4-ethylphenyl
487 Methyl 4-propyl group phenyl
488 Methyl 4-isopropyl phenyl
489 Methyl 4-secondary butyl phenenyl
490 Methyl 4-isobutyl phenenyl
491 Methyl 4-(1,1-dimethyl propyl)-phenyl
492 Methyl 4-ethenylphenyl
493 Methyl 4-pseudoallyl phenyl
494 Methyl 4-fluorophenyl
495 Methyl 4-chloro-phenyl-
496 Methyl 4-bromophenyl
497 Methyl 4-(methyl fluoride) phenyl
498 Methyl 3-(methyl fluoride) phenyl
499 Methyl 2-(methyl fluoride) phenyl
500 Methyl 4-(difluoromethyl) phenyl
501 Methyl 3-(difluoromethyl) phenyl
502 Methyl 2-(difluoromethyl) phenyl
503 Methyl 4-(trifluoromethyl) phenyl
504 Methyl 3-(trifluoromethyl) phenyl
505 Methyl 2-(trifluoromethyl) phenyl
506 Methyl 4-(1-fluoro ethyl)-phenyl
507 Methyl 4-((S)-1-fluoro ethyl)-phenyl
Numbering R 1 Ar
508 Methyl 4-((R)-1-fluoro ethyl)-phenyl
509 Methyl 4-(2-fluoro ethyl)-phenyl
510 Methyl 4-(1,1-, bis-fluoro ethyls)-phenyl
511 Methyl 4-(2,2-, bis-fluoro ethyls)-phenyl
512 Methyl 4-(2,2,2-trifluoroethyl)-phenyl
513 Methyl 4-(3-fluoropropyl)-phenyl
514 Methyl 4-(2-fluoropropyl)-phenyl
515 Methyl 4-((S)-2-fluoropropyl)-phenyl
516 Methyl 4-((R)-2-fluoropropyl)-phenyl
517 Methyl 4-(3,3-, bis-fluoropropyls)-phenyl
518 Methyl 4-(3,3,3-trifluoro propyl)-phenyl
519 Methyl 4-(the fluoro-1-methylethyl of 1-)-phenyl
520 Methyl 4-(the fluoro-1-methylethyl of 2-)-phenyl
521 Methyl 4-(the fluoro-1-methylethyl of (S)-2-)-phenyl
522 Methyl 4-(the fluoro-1-methylethyl of (R)-2-)-phenyl
523 Methyl 4-(the fluoro-1-methylethyl of 2,2-bis-)-phenyl
524 Methyl 4-((S)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
525 Methyl 4-((R)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
526 Methyl 4-(the fluoro-1-methylethyl of 2,2,2-tri-)-phenyl
527 Methyl 4-((S)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
528 Methyl 4-((R)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
529 Methyl 4-(the fluoro-1-methyl fluoride of 2-ethyl)-phenyl
530 Methyl 4-(1-difluoromethyl-2,2-bis-fluoro ethyls)-phenyl
531 Methyl 4-(1,1-dimethyl-2-fluoro ethyl)-phenyl
532 Methyl 4-p-methoxy-phenyl
533 Methyl 4-ethoxyl phenenyl
534 Methyl 4-propoxy-phenyl
535 Methyl 4-isopropyl phenyl
536 Methyl 4-butoxy phenyl
537 Methyl 4-(fluorine methoxyl group)-phenyl
Numbering R 1 Ar
538 Methyl 4-(difluoro-methoxy)-phenyl
539 Methyl 4-(trifluoromethoxy)-phenyl
540 Methyl 3-(trifluoromethoxy)-phenyl
541 Methyl 4-(2-fluorine oxyethyl group)-phenyl
542 Methyl 4-(2,2-difluoroethoxy)-phenyl
543 Methyl 4-(2,2,2-trifluoro ethoxy)-phenyl
544 Methyl 4-(1,1,2,2-tetrafluoro oxyethyl group)-phenyl
545 Methyl 4-cyclopropyl phenyl
546 Methyl 4-cyclobutyl phenyl
547 Methyl 4-cyclopentyl phenyl
548 Methyl 4-(2,2-difluoro cyclopropyl)-phenyl
549 Methyl 3,4-difluorophenyl
550 Methyl 4-bromine-3-fluorophenyl
551 Methyl The bromo-2-fluorophenyl of 4-
552 Methyl 4-is bromo-2,5-difluorophenyl
553 Methyl The fluoro-4-isopropyl phenyl of 2-
554 Methyl The fluoro-4-isopropyl phenyl of 3-
555 Methyl 4-(1-hydroxyl-1-methylethyl)-phenyl
556 Methyl 4-(2-hydroxy-2-methyl propyl group)-phenyl
557 Methyl 4-acetylphenyl
558 Methyl 4-carboxyl phenyl
559 Methyl 4-cyano-phenyl
560 Methyl 4-hydroxy phenyl
561 Methyl 4-(O-benzyl)-phenyl
562 Methyl 4-(2-methoxy ethoxy)-phenyl
563 Methyl 4-(CH 2-N(CH 3) 2)-phenyl
564 Methyl 4-(NH-CO-NH 2)-phenyl
565 Methyl 4-(methylthio group)-phenyl
566 Methyl 4-(fluorine methylthio group)-phenyl
567 Methyl 4-(difluoro methylthio group)-phenyl
Numbering R 1 Ar
568 Methyl 4-(trifluoromethylthio)-phenyl
569 Methyl 4-(methyl sulphonyl)-phenyl
570 Methyl 4-(N-methoxyl group-N-methyl-amino)-phenyl
571 Methyl 4-(methoxyl group is amino)-phenyl
572 Methyl 4-(oxyethyl group is amino)-phenyl
573 Methyl 4-(N-methylamino oxygen base)-phenyl
574 Methyl 4-(N, N-dimethylamino oxygen base)-phenyl
575 Methyl 4-(azetidine-1-yl)-phenyl
576 Methyl 4-(2-methyl azetidine-1-yl)-phenyl
577 Methyl 4-((S)-2-methyl azetidine-1-yl)-phenyl
578 Methyl 4-((R)-2-methyl azetidine-1-yl)-phenyl
579 Methyl 4-(3-fluorine azetidine-1-yl)-phenyl
580 Methyl 4-(3-methoxyl group azetidine-1-yl)-phenyl
581 Methyl 4-(3-hydroxy azetidine-1-yl)-phenyl
582 Methyl 4-(pyrrolidin-1-yl)-phenyl
583 Methyl 4-(pyrrolidin-2-yl)-phenyl
584 Methyl 4-((S)-pyrrolidin-2-yl)-phenyl
585 Methyl 4-((R)-pyrrolidin-2-yl)-phenyl
586 Methyl 4-(pyrrolidin-3-yl)-phenyl
587 Methyl 4-((S)-pyrrolidin-3-yl)-phenyl
588 Methyl 4-((R)-pyrrolidin-3-yl)-phenyl
589 Methyl 4-(2-fluoropyrrolidine-1-yl)-phenyl
590 Methyl 4-((S)-2-fluoropyrrolidine-1-yl)-phenyl
591 Methyl 4-((R)-2-fluoropyrrolidine-1-yl)-phenyl
592 Methyl 4-(3-fluoropyrrolidine-1-yl)-phenyl
593 Methyl 4-((S)-3-fluoropyrrolidine-1-yl)-phenyl
594 Methyl 4-((R)-3-fluoropyrrolidine-1-yl)-phenyl
595 Methyl 4-(2,2-difluoro pyrrolidin-1-yl)-phenyl
596 Methyl 4-(3,3-difluoro pyrrolidin-1-yl)-phenyl
597 Methyl 4-(2-methylpyrrolidin-1-yl)-phenyl
Numbering R 1 Ar
598 Methyl 4-((S)-2-methylpyrrolidin-1-yl)-phenyl
599 Methyl 4-((R)-2-methylpyrrolidin-1-yl)-phenyl
600 Methyl 4-(3-methylpyrrolidin-1-yl)-phenyl
601 Methyl 4-((S)-3-methylpyrrolidin-1-yl)-phenyl
602 Methyl 4-((R)-3-methylpyrrolidin-1-yl)-phenyl
603 Methyl 4-(1-methylpyrrolidin-2-yl)-phenyl
604 Methyl 4-((S)-1-methylpyrrolidin-2-yl)-phenyl
605 Methyl 4-((R)-1-methylpyrrolidin-2-yl)-phenyl
606 Methyl 4-(1-methylpyrrolidin-3-yl)-phenyl
607 Methyl 4-((S)-1-methylpyrrolidin-3-yl)-phenyl
608 Methyl 4-((R)-1-methylpyrrolidin-3-yl)-phenyl
609 Methyl 4-(2,2-dimethyl pyrrolidine-1-yl)-phenyl
610 Methyl 4-(3,3-dimethyl pyrrolidine-1-yl)-phenyl
611 Methyl 4-(2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
612 Methyl 4-((S)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
613 Methyl 4-((R)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
614 Methyl 4-(3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
615 Methyl 4-((S)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
616 Methyl 4-((R)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
617 Methyl 4-(2-oxo-pyrrolidine-1-yl)-phenyl
618 Methyl 4-(2-oxo-oxazolidines-3-yl)-phenyl
619 Methyl 4-(piperidin-1-yl)-phenyl
620 Methyl 4-(pipecoline-1-yl)-phenyl
621 Methyl 4-((S)-pipecoline-1-yl)-phenyl
622 Methyl 4-((R)-pipecoline-1-yl)-phenyl
623 Methyl 4-(piperazine-1-yl)-phenyl
624 Methyl 4-(4-methylpiperazine-1-yl)-phenyl
625 Methyl 4-(morpholine-4-yl)-phenyl
626 Methyl 4-(thiomorpholine-4-yl)-phenyl
627 Methyl 4-(1-oxo-thiomorpholine-4-yl)-phenyl
Numbering R 1 Ar
628 Methyl 4-(1,1-dioxo-thiomorpholine-4-yl)-phenyl
629 Methyl 4-(pyrroles-1-yl)-phenyl
630 Methyl 4-(pyrroles-2-yl)-phenyl
631 Methyl 4-(pyrroles-3-yl)-phenyl
632 Methyl 4-(1-methylpyrrole-2-yl)-phenyl
633 Methyl 4-(1-methylpyrrole-3-yl)-phenyl
634 Methyl 4-(furans-2-yl)-phenyl
635 Methyl 4-(furans-3-yl)-phenyl
636 Methyl 4-(thiophene-2-yl)-phenyl
637 Methyl 4-(thiene-3-yl-)-phenyl
638 Methyl 4-(5-propyl group thiophene-2-yl)-phenyl
639 Methyl 4-(pyrazol-1-yl)-phenyl
640 Methyl 4-(pyrazole-3-yl)-phenyl
641 Methyl 4-(pyrazoles-4-yl)-phenyl
642 Methyl 4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl
643 Methyl 4-(1-ethyl-1H-pyrazoles-4-yl)-phenyl
644 Methyl 4-(1-methyl isophthalic acid H-pyrazoles-5-yl)-phenyl
645 Methyl 4-(1H-imidazoles-2-yl)-phenyl
646 Methyl 4-(imidazoles-1-yl)-phenyl
647 Methyl 4-(1-Methylimidazole-2-yl)-phenyl
648 Methyl 4-(oxazole-2-yl)-phenyl
649 Methyl 4-(oxazole-4-yl)-phenyl
650 Methyl 4-(oxazole-5-yl)-phenyl
651 Methyl 4-(isoxazole-3-base)-phenyl
652 Methyl 4-(isoxazole-4-base)-phenyl
653 Methyl 4-(isoxazole-5-base)-phenyl
654 Methyl 4-([1,2,3]-triazol-1-yl)-phenyl
655 Methyl 4-([1,2,4]-triazol-1-yl)-phenyl
656 Methyl 4-([1,2,3]-triazole-2-yl)-phenyl
657 Methyl 4-(4H-[1,2,4]-triazole-3-yl)-phenyl
Numbering R 1 Ar
658 Methyl 4-([1,2,4]-triazole-4-yl)-phenyl
659 Methyl 4-(2H-[1,2,3]-triazole-4-yl)-phenyl
660 Methyl 4-(4-methyl-4H-[1,2,4]-triazole-3-yl)-phenyl
661 Methyl 4-(2-methyl-2H-[1,2,3]-triazole-4-yl)-phenyl
662 Methyl 4-([1,3,4]-oxadiazoles-2-yl)-phenyl
663 Methyl 4-([1,2,4]-oxadiazoles-3-yl)-phenyl
664 Methyl 4-([1,2,4]-oxadiazoles-5-yl)-phenyl
665 Methyl 4-([1,2,3]-oxadiazoles-4-yl)-phenyl
666 Methyl 4-([1,2,3]-oxadiazoles-5-yl)-phenyl
667 Methyl 4-([1,2,3]-thiadiazoles-4-yl)-phenyl
668 Methyl 4-(1H-TETRAZOLE-5-yl)-phenyl
669 Methyl 4-(tetrazolium-1-yl)-phenyl
670 Methyl 4-(2-methyl-2H-tetrazolium-5-yl)-phenyl
671 Methyl 4-(1-methyl isophthalic acid H-tetrazolium-5-yl)-phenyl
672 Methyl 4-furazan-3-base-phenyl
673 Methyl 4-(pyridine-2-yl)-phenyl
674 Methyl 4-(pyridin-3-yl)-phenyl
675 Methyl 4-(pyridin-4-yl)-phenyl
676 Methyl 4-(pyrimidine-2-base)-phenyl
677 Methyl 4-(pyrimidine-4-yl)-phenyl
678 Methyl 4-(pyrimidine-5-yl)-phenyl
679 Methyl 5-isopropyl sulfenyl benzene-2-base
680 Methyl 2-chlorothiophene-5-base
681 Methyl 2,5-dichloro-thiophene-4-base
682 Methyl 2,3-dichloro-thiophene-5-base
683 Methyl The chloro-3-nitrothiophene-5-of 2-base
684 Methyl 2-(phenyl sulfonyl)-thiophene-5-base
685 Methyl 2-(pyridine-2-yl) thiophene-5-base
686 Methyl 2-(5-(trifluoromethyl) isoxazole-3-base)-thiophene-5-base
687 Methyl 2-(2-methylthiazol-4-yl)-thiophene-5-base
Numbering R 1 Ar
688 Methyl 1-methyl isophthalic acid H-imidazol-4 yl
689 Methyl 1,2-dimethyl-1H-imidazol-4 yl
690 Methyl 3,5-dimethyl isoxazole-4-base
691 Methyl Thiazol-2-yl
692 Methyl 4-methylthiazol-2-base
693 Methyl 4-sec.-propyl thiazol-2-yl
694 Methyl 4-trifluoromethyl thiazole-2-base
695 Methyl 5-methylthiazol-2-base
696 Methyl 5-sec.-propyl thiazol-2-yl
697 Methyl 5-trifluoromethyl thiazole-2-base
698 Methyl 2,4-dimethylthiazole-5-base
699 Methyl 2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-base
700 Methyl 4H-[1,2,4] triazole-3-base
701 Methyl 5-methyl-4H-[1,2,4] triazole-3-base
702 Methyl 4-methyl-4H-[1,2,4] triazole-3-base
703 Methyl 5-sec.-propyl-4H-[1,2,4] triazole-3-base
704 Methyl 5-trifluoromethyl-4H-[1,2,4] triazole-3-base
705 Methyl 4,5-dimethyl-4H-[1,2,4] triazole-3-base
706 Methyl 5-isopropyl-4-methyl-4H-[1,2,4] triazole-3-base
707 Methyl 5-trifluoromethyl-4-methyl-4H-[1,2,4] triazole-3-base
708 Methyl [1,3,4] thiadiazoles-2-base
709 Methyl 5-methyl-[1,3,4] thiadiazoles-2-base
710 Methyl 5-sec.-propyl-[1,3,4] thiadiazoles-2-base
711 Methyl 5-trifluoromethyl-[1,3,4] thiadiazoles-2-base
712 Methyl The bromo-2-chloropyridine-5-of 3-base
713 Methyl 2-(4-morpholino)-pyridine-5-base
714 Methyl 2-phenoxypyridines-5-base
715 Methyl (2-sec.-propyl)-pyrimidine-5-base
716 Methyl (5-sec.-propyl)-pyrimidine-2-base
717 Methyl 8-quinolyl
Numbering R 1 Ar
718 Methyl 5-isoquinolyl
719 Methyl 2-(trifluoroacetyl group)-1,2,3,4-tetrahydroisoquinoline-7-base
720 Methyl The chloro-3-methylbenzene thiophthene-2-of 5-base
721 Methyl 3,4-dihydro-4-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazinyl
722 Methyl Benzothiazol-6-yl
723 Methyl Benzo [2,1,3] oxadiazole-4-bases
724 Methyl 5-chlorobenzene is [2,1,3] oxadiazole-4-bases also
725 Methyl 7-chlorobenzene is [2,1,3] oxadiazole-4-bases also
726 Methyl Benzo [2,1,3] thiadiazoles-4-base
727 H 4-aminomethyl phenyl
728 H 4-ethylphenyl
729 H 4-propyl group phenyl
730 H 4-isopropyl phenyl
731 H 4-secondary butyl phenenyl
732 H 4-isobutyl phenenyl
733 H 4-(1,1-dimethyl propyl)-phenyl
734 H 4-ethenylphenyl
735 H 4-pseudoallyl phenyl
736 H 4-fluorophenyl
737 H 4-chloro-phenyl-
738 H 4-bromophenyl
739 H 4-(methyl fluoride) phenyl
740 H 3-(methyl fluoride) phenyl
741 H 2-(methyl fluoride) phenyl
742 H 4-(difluoromethyl) phenyl
743 H 3-(difluoromethyl) phenyl
744 H 2-(difluoromethyl) phenyl
745 H 4-(trifluoromethyl) phenyl
746 H 3-(trifluoromethyl) phenyl
747 H 2-(trifluoromethyl) phenyl
Numbering R 1 Ar
748 H 4-(1-fluoro ethyl)-phenyl
749 H 4-((S)-1-fluoro ethyl)-phenyl
750 H 4-((R)-1-fluoro ethyl)-phenyl
751 H 4-(2-fluoro ethyl)-phenyl
752 H 4-(1,1-, bis-fluoro ethyls)-phenyl
753 H 4-(2,2-, bis-fluoro ethyls)-phenyl
754 H 4-(2,2,2-trifluoroethyl)-phenyl
755 H 4-(3-fluoropropyl)-phenyl
756 H 4-(2-fluoropropyl)-phenyl
757 H 4-((S)-2-fluoropropyl)-phenyl
758 H 4-((R)-2-fluoropropyl)-phenyl
759 H 4-(3,3-, bis-fluoropropyls)-phenyl
760 H 4-(3,3,3-trifluoro propyl)-phenyl
761 H 4-(the fluoro-1-methylethyl of 1-)-phenyl
762 H 4-(the fluoro-1-methylethyl of 2-)-phenyl
763 H 4-(the fluoro-1-methylethyl of (S)-2-)-phenyl
764 H 4-(the fluoro-1-methylethyl of (R)-2-)-phenyl
765 H 4-(the fluoro-1-methylethyl of 2,2-bis-)-phenyl
766 H 4-((S)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
767 H 4-((R)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
768 H 4-(the fluoro-1-methylethyl of 2,2,2-tri-)-phenyl
769 H 4-((S)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
770 H 4-((R)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
771 H 4-(the fluoro-1-methyl fluoride of 2-ethyl)-phenyl
772 H 4-(1-difluoromethyl-2,2-bis-fluoro ethyls)-phenyl
773 H 4-(1,1-dimethyl-2-fluoro ethyl)-phenyl
774 H 4-p-methoxy-phenyl
775 H 4-ethoxyl phenenyl
776 H 4-propoxy-phenyl
777 H 4-isopropyl phenyl
Numbering R 1 Ar
778 H 4-butoxy phenyl
779 H 4-(fluorine methoxyl group)-phenyl
780 H 4-(difluoro-methoxy)-phenyl
781 H 4-(trifluoromethoxy)-phenyl
782 H 3-(trifluoromethoxy)-phenyl
783 H 4-(2-fluorine oxyethyl group)-phenyl
784 H 4-(2,2-difluoroethoxy)-phenyl
785 H 4-(2,2,2-trifluoro ethoxy)-phenyl
786 H 4-(1,1,2,2-tetrafluoro oxyethyl group)-phenyl
787 H 4-cyclopropyl phenyl
788 H 4-cyclobutyl phenyl
789 H 4-cyclopentyl phenyl
790 H 4-(2,2-difluoro cyclopropyl)-phenyl
791 H 3,4-difluorophenyl
792 H 4-bromine-3-fluorophenyl
793 H The bromo-2-fluorophenyl of 4-
794 H 4-is bromo-2,5-difluorophenyl
795 H The fluoro-4-isopropyl phenyl of 2-
796 H The fluoro-4-isopropyl phenyl of 3-
797 H 4-(1-hydroxyl-1-methylethyl)-phenyl
798 H 4-(2-hydroxy-2-methyl propyl group)-phenyl
799 H 4-acetylphenyl
800 H 4-carboxyl phenyl
801 H 4-cyano-phenyl
802 H 4-hydroxy phenyl
803 H 4-(O-benzyl)-phenyl
804 H 4-(2-methoxy ethoxy)-phenyl
805 H 4-(CH 2-N(CH 3) 2)-phenyl
806 H 4-(NH-CO-NH 2)-phenyl
807 H 4-(methylthio group)-phenyl
Numbering R 1 Ar
808 H 4-(fluorine methylthio group)-phenyl
809 H 4-(difluoro methylthio group)-phenyl
810 H 4-(trifluoromethylthio)-phenyl
811 H 4-(methyl sulphonyl)-phenyl
812 H 4-(N-methoxyl group-N-methyl-amino)-phenyl
813 H 4-(methoxyl group is amino)-phenyl
814 H 4-(oxyethyl group is amino)-phenyl
815 H 4-(N-methylamino oxygen base)-phenyl
816 H 4-(N, N-dimethylamino oxygen base)-phenyl
817 H 4-(azetidine-1-yl)-phenyl
818 H 4-(2-methyl azetidine-1-yl)-phenyl
819 H 4-((S)-2-methyl azetidine-1-yl)-phenyl
820 H 4-((R)-2-methyl azetidine-1-yl)-phenyl
821 H 4-(3-fluorine azetidine-1-yl)-phenyl
822 H 4-(3-methoxyl group azetidine-1-yl)-phenyl
823 H 4-(3-hydroxy azetidine-1-yl)-phenyl
824 H 4-(pyrrolidin-1-yl)-phenyl
825 H 4-(pyrrolidin-2-yl)-phenyl
826 H 4-((S)-pyrrolidin-2-yl)-phenyl
827 H 4-((R)-pyrrolidin-2-yl)-phenyl
828 H 4-(pyrrolidin-3-yl)-phenyl
829 H 4-((S)-pyrrolidin-3-yl)-phenyl
830 H 4-((R)-pyrrolidin-3-yl)-phenyl
831 H 4-(2-fluoropyrrolidine-1-yl)-phenyl
832 H 4-((S)-2-fluoropyrrolidine-1-yl)-phenyl
833 H 4-((R)-2-fluoropyrrolidine-1-yl)-phenyl
834 H 4-(3-fluoropyrrolidine-1-yl)-phenyl
835 H 4-((S)-3-fluoropyrrolidine-1-yl)-phenyl
836 H 4-((R)-3-fluoropyrrolidine-1-yl)-phenyl
837 H 4-(2,2-difluoro pyrrolidin-1-yl)-phenyl
Numbering R 1 Ar
838 H 4-(3,3-difluoro pyrrolidin-1-yl)-phenyl
839 H 4-(2-methylpyrrolidin-1-yl)-phenyl
840 H 4-((S)-2-methylpyrrolidin-1-yl)-phenyl
841 H 4-((R)-2-methylpyrrolidin-1-yl)-phenyl
842 H 4-(3-methylpyrrolidin-1-yl)-phenyl
843 H 4-((S)-3-methylpyrrolidin-1-yl)-phenyl
844 H 4-((R)-3-methylpyrrolidin-1-yl)-phenyl
845 H 4-(1-methylpyrrolidin-2-yl)-phenyl
846 H 4-((S)-1-methylpyrrolidin-2-yl)-phenyl
847 H 4-((R)-1-methylpyrrolidin-2-yl)-phenyl
848 H 4-(1-methylpyrrolidin-3-yl)-phenyl
849 H 4-((S)-1-methylpyrrolidin-3-yl)-phenyl
850 H 4-((R)-1-methylpyrrolidin-3-yl)-phenyl
851 H 4-(2,2-dimethyl pyrrolidine-1-yl)-phenyl
852 H 4-(3,3-dimethyl pyrrolidine-1-yl)-phenyl
853 H 4-(2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
854 H 4-((S)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
855 H 4-((R)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
856 H 4-(3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
857 H 4-((S)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
858 H 4-((R)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
859 H 4-(2-oxo-pyrrolidine-1-yl)-phenyl
860 H 4-(2-oxo-oxazolidines-3-yl)-phenyl
861 H 4-(piperidin-1-yl)-phenyl
862 H 4-(pipecoline-1-yl)-phenyl
863 H 4-((S)-pipecoline-1-yl)-phenyl
864 H 4-((R)-pipecoline-1-yl)-phenyl
865 H 4-(piperazine-1-yl)-phenyl
866 H 4-(4-methylpiperazine-1-yl)-phenyl
867 H 4-(morpholine-4-yl)-phenyl
Numbering R 1 Ar
868 H 4-(thiomorpholine-4-yl)-phenyl
869 H 4-(1-oxo-thiomorpholine-4-yl)-phenyl
870 H 4-(1,1-dioxo-thiomorpholine-4-yl)-phenyl
871 H 4-(pyrroles-1-yl)-phenyl
872 H 4-(pyrroles-2-yl)-phenyl
873 H 4-(pyrroles-3-yl)-phenyl
874 H 4-(1-methylpyrrole-2-yl)-phenyl
875 H 4-(1-methylpyrrole-3-yl)-phenyl
876 H 4-(furans-2-yl)-phenyl
877 H 4-(furans-3-yl)-phenyl
878 H 4-(thiophene-2-yl)-phenyl
879 H 4-(thiene-3-yl-)-phenyl
880 H 4-(5-propyl group thiophene-2-yl)-phenyl
881 H 4-(pyrazol-1-yl)-phenyl
882 H 4-(pyrazole-3-yl)-phenyl
883 H 4-(pyrazoles-4-yl)-phenyl
884 H 4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl
885 H 4-(1-ethyl-1H-pyrazoles-4-yl)-phenyl
886 H 4-(1-methyl isophthalic acid H-pyrazoles-5-yl)-phenyl
887 H 4-(1H-imidazoles-2-yl)-phenyl
888 H 4-(imidazoles-1-yl)-phenyl
889 H 4-(1-Methylimidazole-2-yl)-phenyl
890 H 4-(oxazole-2-yl)-phenyl
891 H 4-(oxazole-4-yl)-phenyl
892 H 4-(oxazole-5-yl)-phenyl
893 H 4-(isoxazole-3-base)-phenyl
894 H 4-(isoxazole-4-base)-phenyl
895 H 4-(isoxazole-5-base)-phenyl
896 H 4-([1,2,3]-triazol-1-yl)-phenyl
897 H 4-([1,2,4]-triazol-1-yl)-phenyl
Numbering R 1 Ar
898 H 4-([1,2,3]-triazole-2-yl)-phenyl
899 H 4-(4H-[1,2,4]-triazole-3-yl)-phenyl
900 H 4-([1,2,4]-triazole-4-yl)-phenyl
901 H 4-(2H-[1,2,3]-triazole-4-yl)-phenyl
902 H 4-(4-methyl-4H-[1,2,4]-triazole-3-yl)-phenyl
903 H 4-(2-methyl-2H-[1,2,3]-triazole-4-yl)-phenyl
904 H 4-([1,3,4]-oxadiazoles-2-yl)-phenyl
905 H 4-([1,2,4]-oxadiazoles-3-yl)-phenyl
906 H 4-([1,2,4]-oxadiazoles-5-yl)-phenyl
907 H 4-([1,2,3]-oxadiazoles-4-yl)-phenyl
908 H 4-([1,2,3]-oxadiazoles-5-yl)-phenyl
909 H 4-([1,2,3]-thiadiazoles-4-yl)-phenyl
910 H 4-(1H-TETRAZOLE-5-yl)-phenyl
911 H 4-(tetrazolium-1-yl)-phenyl
912 H 4-(2-methyl-2H-tetrazolium-5-yl)-phenyl
913 H 4-(1-methyl isophthalic acid H-tetrazolium-5-yl)-phenyl
914 H 4-furazan-3-base-phenyl
915 H 4-(pyridine-2-yl)-phenyl
916 H 4-(pyridin-3-yl)-phenyl
917 H 4-(pyridin-4-yl)-phenyl
918 H 4-(pyrimidine-2-base)-phenyl
919 H 4-(pyrimidine-4-yl)-phenyl
920 H 4-(pyrimidine-5-yl)-phenyl
921 H 5-isopropyl sulfenyl benzene-2-base
922 H 2-chlorothiophene-5-base
923 H 2,5-dichloro-thiophene-4-base
924 H 2,3-dichloro-thiophene-5-base
925 H The chloro-3-nitrothiophene-5-of 2-base
926 H 2-(phenyl sulfonyl)-thiophene-5-base
927 H 2-(pyridine-2-yl) thiophene-5-base
Numbering R 1 Ar
928 H 2-(5-(trifluoromethyl) isoxazole-3-base)-thiophene-5-base
929 H 2-(2-methylthiazol-4-yl)-thiophene-5-base
930 H 1-methyl isophthalic acid H-imidazol-4 yl
931 H 1,2-dimethyl-1H-imidazol-4 yl
932 H 3,5-dimethyl isoxazole-4-base
933 H Thiazol-2-yl
934 H 4-methylthiazol-2-base
935 H 4-sec.-propyl thiazol-2-yl
936 H 4-trifluoromethyl thiazole-2-base
937 H 5-methylthiazol-2-base
938 H 5-sec.-propyl thiazol-2-yl
939 H 5-trifluoromethyl thiazole-2-base
940 H 2,4-dimethylthiazole-5-base
941 H 2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-base
942 H 4H-[1,2,4] triazole-3-base
943 H 5-methyl-4H-[1,2,4] triazole-3-base
944 H 4-methyl-4H-[1,2,4] triazole-3-base
945 H 5-sec.-propyl-4H-[1,2,4] triazole-3-base
946 H 5-trifluoromethyl-4H-[1,2,4] triazole-3-base
947 H 4,5-dimethyl-4H-[1,2,4] triazole-3-base
948 H 5-isopropyl-4-methyl-4H-[1,2,4] triazole-3-base
949 H 5-trifluoromethyl-4-methyl-4H-[1,2,4] triazole-3-base
950 H [1,3,4] thiadiazoles-2-base
951 H 5-methyl-[1,3,4] thiadiazoles-2-base
952 H 5-sec.-propyl-[1,3,4] thiadiazoles-2-base
953 H 5-trifluoromethyl-[1,3,4] thiadiazoles-2-base
954 H The bromo-2-chloropyridine-5-of 3-base
955 H 2-(4-morpholino)-pyridine-5-base
956 H 2-phenoxypyridines-5-base
957 H (2-sec.-propyl)-pyrimidine-5-base
Numbering R 1 Ar
958 H (5-sec.-propyl)-pyrimidine-2-base
959 H 8-quinolyl
960 H 5-isoquinolyl
961 H 2-(trifluoroacetyl group)-1,2,3,4-tetrahydroisoquinoline-7-base
962 H The chloro-3-methylbenzene thiophthene-2-of 5-base
963 H 3,4-dihydro-4-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazinyl
964 H Benzothiazol-6-yl
965 H Benzo [2,1,3] oxadiazole-4-bases
966 H 5-chlorobenzene is [2,1,3] oxadiazole-4-bases also
967 H 7-chlorobenzene is [2,1,3] oxadiazole-4-bases also
968 H Benzo [2,1,3] thiadiazoles-4-base
969 3-fluoropropyl 4-aminomethyl phenyl
970 3-fluoropropyl 4-ethylphenyl
971 3-fluoropropyl 4-propyl group phenyl
972 3-fluoropropyl 4-isopropyl phenyl
973 3-fluoropropyl 4-secondary butyl phenenyl
974 3-fluoropropyl 4-isobutyl phenenyl
975 3-fluoropropyl 4-(1,1-dimethyl propyl)-phenyl
976 3-fluoropropyl 4-ethenylphenyl
977 3-fluoropropyl 4-pseudoallyl phenyl
978 3-fluoropropyl 4-fluorophenyl
979 3-fluoropropyl 4-chloro-phenyl-
980 3-fluoropropyl 4-bromophenyl
981 3-fluoropropyl 4-(methyl fluoride) phenyl
982 3-fluoropropyl 3-(methyl fluoride) phenyl
983 3-fluoropropyl 2-(methyl fluoride) phenyl
984 3-fluoropropyl 4-(difluoromethyl) phenyl
985 3-fluoropropyl 3-(difluoromethyl) phenyl
986 3-fluoropropyl 2-(difluoromethyl) phenyl
987 3-fluoropropyl 4-(trifluoromethyl) phenyl
Numbering R 1 Ar
988 3-fluoropropyl 3-(trifluoromethyl) phenyl
989 3-fluoropropyl 2-(trifluoromethyl) phenyl
990 3-fluoropropyl 4-(1-fluoro ethyl)-phenyl
991 3-fluoropropyl 4-((S)-1-fluoro ethyl)-phenyl
992 3-fluoropropyl 4-((R)-1-fluoro ethyl)-phenyl
993 3-fluoropropyl 4-(2-fluoro ethyl)-phenyl
994 3-fluoropropyl 4-(1,1-, bis-fluoro ethyls)-phenyl
995 3-fluoropropyl 4-(2,2-, bis-fluoro ethyls)-phenyl
996 3-fluoropropyl 4-(2,2,2-trifluoroethyl)-phenyl
997 3-fluoropropyl 4-(3-fluoropropyl)-phenyl
998 3-fluoropropyl 4-(2-fluoropropyl)-phenyl
999 3-fluoropropyl 4-((S)-2-fluoropropyl)-phenyl
1000 3-fluoropropyl 4-((R)-2-fluoropropyl)-phenyl
1001 3-fluoropropyl 4-(3,3-, bis-fluoropropyls)-phenyl
1002 3-fluoropropyl 4-(3,3,3-trifluoro propyl)-phenyl
1003 3-fluoropropyl 4-(the fluoro-1-methylethyl of 1-)-phenyl
1004 3-fluoropropyl 4-(the fluoro-1-methylethyl of 2-)-phenyl
1005 3-fluoropropyl 4-(the fluoro-1-methylethyl of (S)-2-)-phenyl
1006 3-fluoropropyl 4-(the fluoro-1-methylethyl of (R)-2-)-phenyl
1007 3-fluoropropyl 4-(the fluoro-1-methylethyl of 2,2-bis-)-phenyl
1008 3-fluoropropyl 4-((S)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
1009 3-fluoropropyl 4-((R)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
1010 3-fluoropropyl 4-(the fluoro-1-methylethyl of 2,2,2-tri-)-phenyl
1011 3-fluoropropyl 4-((S)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
1012 3-fluoropropyl 4-((R)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
1013 3-fluoropropyl 4-(the fluoro-1-methyl fluoride of 2-ethyl)-phenyl
1014 3-fluoropropyl 4-(1-difluoromethyl-2,2-bis-fluoro ethyls)-phenyl
1015 3-fluoropropyl 4-(1,1-dimethyl-2-fluoro ethyl)-phenyl
1016 3-fluoropropyl 4-p-methoxy-phenyl
1017 3-fluoropropyl 4-ethoxyl phenenyl
Numbering R 1 Ar
1018 3-fluoropropyl 4-propoxy-phenyl
1019 3-fluoropropyl 4-isopropyl phenyl
1020 3-fluoropropyl 4-butoxy phenyl
1021 3-fluoropropyl 4-(fluorine methoxyl group)-phenyl
1022 3-fluoropropyl 4-(difluoro-methoxy)-phenyl
1023 3-fluoropropyl 4-(trifluoromethoxy)-phenyl
1024 3-fluoropropyl 3-(trifluoromethoxy)-phenyl
1025 3-fluoropropyl 4-(2-fluorine oxyethyl group)-phenyl
1026 3-fluoropropyl 4-(2,2-difluoroethoxy)-phenyl
1027 3-fluoropropyl 4-(2,2,2-trifluoro ethoxy)-phenyl
1028 3-fluoropropyl 4-(1,1,2,2-tetrafluoro oxyethyl group)-phenyl
1029 3-fluoropropyl 4-cyclopropyl phenyl
1030 3-fluoropropyl 4-cyclobutyl phenyl
1031 3-fluoropropyl 4-cyclopentyl phenyl
1032 3-fluoropropyl 4-(2,2-difluoro cyclopropyl)-phenyl
1033 3-fluoropropyl 3,4-difluorophenyl
1034 3-fluoropropyl 4-bromine-3-fluorophenyl
1035 3-fluoropropyl The bromo-2-fluorophenyl of 4-
1036 3-fluoropropyl 4-is bromo-2,5-difluorophenyl
1037 3-fluoropropyl The fluoro-4-isopropyl phenyl of 2-
1038 3-fluoropropyl The fluoro-4-isopropyl phenyl of 3-
1039 3-fluoropropyl 4-(1-hydroxyl-1-methylethyl)-phenyl
1040 3-fluoropropyl 4-(2-hydroxy-2-methyl propyl group)-phenyl
1041 3-fluoropropyl 4-acetylphenyl
1042 3-fluoropropyl 4-carboxyl phenyl
1043 3-fluoropropyl 4-cyano-phenyl
1044 3-fluoropropyl 4-hydroxy phenyl
1045 3-fluoropropyl 4-(O-benzyl)-phenyl
1046 3-fluoropropyl 4-(2-methoxy ethoxy)-phenyl
1047 3-fluoropropyl 4-(CH 2-N(CH 3) 2)-phenyl
Numbering R 1 Ar
1048 3-fluoropropyl 4-(NH-CO-NH 2)-phenyl
1049 3-fluoropropyl 4-(methylthio group)-phenyl
1050 3-fluoropropyl 4-(fluorine methylthio group)-phenyl
1051 3-fluoropropyl 4-(difluoro methylthio group)-phenyl
1052 3-fluoropropyl 4-(trifluoromethylthio)-phenyl
1053 3-fluoropropyl 4-(methyl sulphonyl)-phenyl
1054 3-fluoropropyl 4-(N-methoxyl group-N-methyl-amino)-phenyl
1055 3-fluoropropyl 4-(methoxyl group is amino)-phenyl
1056 3-fluoropropyl 4-(oxyethyl group is amino)-phenyl
1057 3-fluoropropyl 4-(N-methylamino oxygen base)-phenyl
1058 3-fluoropropyl 4-(N, N-dimethylamino oxygen base)-phenyl
1059 3-fluoropropyl 4-(azetidine-1-yl)-phenyl
1060 3-fluoropropyl 4-(2-methyl azetidine-1-yl)-phenyl
1061 3-fluoropropyl 4-((S)-2-methyl azetidine-1-yl)-phenyl
1062 3-fluoropropyl 4-((R)-2-methyl azetidine-1-yl)-phenyl
1063 3-fluoropropyl 4-(3-fluorine azetidine-1-yl)-phenyl
1064 3-fluoropropyl 4-(3-methoxyl group azetidine-1-yl)-phenyl
1065 3-fluoropropyl 4-(3-hydroxy azetidine-1-yl)-phenyl
1066 3-fluoropropyl 4-(pyrrolidin-1-yl)-phenyl
1067 3-fluoropropyl 4-(pyrrolidin-2-yl)-phenyl
1068 3-fluoropropyl 4-((S)-pyrrolidin-2-yl)-phenyl
1069 3-fluoropropyl 4-((R)-pyrrolidin-2-yl)-phenyl
1070 3-fluoropropyl 4-(pyrrolidin-3-yl)-phenyl
1071 3-fluoropropyl 4-((S)-pyrrolidin-3-yl)-phenyl
1072 3-fluoropropyl 4-((R)-pyrrolidin-3-yl)-phenyl
1073 3-fluoropropyl 4-(2-fluoropyrrolidine-1-yl)-phenyl
1074 3-fluoropropyl 4-((S)-2-fluoropyrrolidine-1-yl)-phenyl
1075 3-fluoropropyl 4-((R)-2-fluoropyrrolidine-1-yl)-phenyl
1076 3-fluoropropyl 4-(3-fluoropyrrolidine-1-yl)-phenyl
1077 3-fluoropropyl 4-((S)-3-fluoropyrrolidine-1-yl)-phenyl
Numbering R 1 Ar
1078 3-fluoropropyl 4-((R)-3-fluoropyrrolidine-1-yl)-phenyl
1079 3-fluoropropyl 4-(2,2-difluoro pyrrolidin-1-yl)-phenyl
1080 3-fluoropropyl 4-(3,3-difluoro pyrrolidin-1-yl)-phenyl
1081 3-fluoropropyl 4-(2-methylpyrrolidin-1-yl)-phenyl
1082 3-fluoropropyl 4-((S)-2-methylpyrrolidin-1-yl)-phenyl
1083 3-fluoropropyl 4-((R)-2-methylpyrrolidin-1-yl)-phenyl
1084 3-fluoropropyl 4-(3-methylpyrrolidin-1-yl)-phenyl
1085 3-fluoropropyl 4-((S)-3-methylpyrrolidin-1-yl)-phenyl
1086 3-fluoropropyl 4-((R)-3-methylpyrrolidin-1-yl)-phenyl
1087 3-fluoropropyl 4-(1-methylpyrrolidin-2-yl)-phenyl
1088 3-fluoropropyl 4-((S)-1-methylpyrrolidin-2-yl)-phenyl
1089 3-fluoropropyl 4-((R)-1-methylpyrrolidin-2-yl)-phenyl
1090 3-fluoropropyl 4-(1-methylpyrrolidin-3-yl)-phenyl
1091 3-fluoropropyl 4-((S)-1-methylpyrrolidin-3-yl)-phenyl
1092 3-fluoropropyl 4-((R)-1-methylpyrrolidin-3-yl)-phenyl
1093 3-fluoropropyl 4-(2,2-dimethyl pyrrolidine-1-yl)-phenyl
1094 3-fluoropropyl 4-(3,3-dimethyl pyrrolidine-1-yl)-phenyl
1095 3-fluoropropyl 4-(2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1096 3-fluoropropyl 4-((S)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1097 3-fluoropropyl 4-((R)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1098 3-fluoropropyl 4-(3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1099 3-fluoropropyl 4-((S)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1100 3-fluoropropyl 4-((R)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1101 3-fluoropropyl 4-(2-oxo-pyrrolidine-1-yl)-phenyl
1102 3-fluoropropyl 4-(2-oxo-oxazolidines-3-yl)-phenyl
1103 3-fluoropropyl 4-(piperidin-1-yl)-phenyl
1104 3-fluoropropyl 4-(pipecoline-1-yl)-phenyl
1105 3-fluoropropyl 4-((S)-pipecoline-1-yl)-phenyl
1106 3-fluoropropyl 4-((R)-pipecoline-1-yl)-phenyl
1107 3-fluoropropyl 4-(piperazine-1-yl)-phenyl
Numbering R 1 Ar
1108 3-fluoropropyl 4-(4-methylpiperazine-1-yl)-phenyl
1109 3-fluoropropyl 4-(morpholine-4-yl)-phenyl
1110 3-fluoropropyl 4-(thiomorpholine-4-yl)-phenyl
1111 3-fluoropropyl 4-(1-oxo-thiomorpholine-4-yl)-phenyl
1112 3-fluoropropyl 4-(1,1-dioxo-thiomorpholine-4-yl)-phenyl
1113 3-fluoropropyl 4-(pyrroles-1-yl)-phenyl
1114 3-fluoropropyl 4-(pyrroles-2-yl)-phenyl
1115 3-fluoropropyl 4-(pyrroles-3-yl)-phenyl
1116 3-fluoropropyl 4-(1-methylpyrrole-2-yl)-phenyl
1117 3-fluoropropyl 4-(1-methylpyrrole-3-yl)-phenyl
1118 3-fluoropropyl 4-(furans-2-yl)-phenyl
1119 3-fluoropropyl 4-(furans-3-yl)-phenyl
1120 3-fluoropropyl 4-(thiophene-2-yl)-phenyl
1121 3-fluoropropyl 4-(thiene-3-yl-)-phenyl
1122 3-fluoropropyl 4-(5-propyl group thiophene-2-yl)-phenyl
1123 3-fluoropropyl 4-(pyrazol-1-yl)-phenyl
1124 3-fluoropropyl 4-(pyrazole-3-yl)-phenyl
1125 3-fluoropropyl 4-(pyrazoles-4-yl)-phenyl
1126 3-fluoropropyl 4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl
1127 3-fluoropropyl 4-(1-ethyl-1H-pyrazoles-4-yl)-phenyl
1128 3-fluoropropyl 4-(1-methyl isophthalic acid H-pyrazoles-5-yl)-phenyl
1129 3-fluoropropyl 4-(1H-imidazoles-2-yl)-phenyl
1130 3-fluoropropyl 4-(imidazoles-1-yl)-phenyl
1131 3-fluoropropyl 4-(1-Methylimidazole-2-yl)-phenyl
1132 3-fluoropropyl 4-(oxazole-2-yl)-phenyl
1133 3-fluoropropyl 4-(oxazole-4-yl)-phenyl
1134 3-fluoropropyl 4-(oxazole-5-yl)-phenyl
1135 3-fluoropropyl 4-(isoxazole-3-base)-phenyl
1136 3-fluoropropyl 4-(isoxazole-4-base)-phenyl
1137 3-fluoropropyl 4-(isoxazole-5-base)-phenyl
Numbering R 1 Ar
1138 3-fluoropropyl 4-([1,2,3]-triazol-1-yl)-phenyl
1139 3-fluoropropyl 4-([1,2,4]-triazol-1-yl)-phenyl
1140 3-fluoropropyl 4-([1,2,3]-triazole-2-yl)-phenyl
1141 3-fluoropropyl 4-(4H-[1,2,4]-triazole-3-yl)-phenyl
1142 3-fluoropropyl 4-([1,2,4]-triazole-4-yl)-phenyl
1143 3-fluoropropyl 4-(2H-[1,2,3]-triazole-4-yl)-phenyl
1144 3-fluoropropyl 4-(4-methyl-4H-[1,2,4]-triazole-3-yl)-phenyl
1145 3-fluoropropyl 4-(2-methyl-2H-[1,2,3]-triazole-4-yl)-phenyl
1146 3-fluoropropyl 4-([1,3,4]-oxadiazoles-2-yl)-phenyl
1147 3-fluoropropyl 4-([1,2,4]-oxadiazoles-3-yl)-phenyl
1148 3-fluoropropyl 4-([1,2,4]-oxadiazoles-5-yl)-phenyl
1149 3-fluoropropyl 4-([1,2,3]-oxadiazoles-4-yl)-phenyl
1150 3-fluoropropyl 4-([1,2,3]-oxadiazoles-5-yl)-phenyl
1151 3-fluoropropyl 4-([1,2,3]-thiadiazoles-4-yl)-phenyl
1152 3-fluoropropyl 4-(1H-TETRAZOLE-5-yl)-phenyl
1153 3-fluoropropyl 4-(tetrazolium-1-yl)-phenyl
1154 3-fluoropropyl 4-(2-methyl-2H-tetrazolium-5-yl)-phenyl
1155 3-fluoropropyl 4-(1-methyl isophthalic acid H-tetrazolium-5-yl)-phenyl
1156 3-fluoropropyl 4-furazan-3-base-phenyl
1157 3-fluoropropyl 4-(pyridine-2-yl)-phenyl
1158 3-fluoropropyl 4-(pyridin-3-yl)-phenyl
1159 3-fluoropropyl 4-(pyridin-4-yl)-phenyl
1160 3-fluoropropyl 4-(pyrimidine-2-base)-phenyl
1161 3-fluoropropyl 4-(pyrimidine-4-yl)-phenyl
1162 3-fluoropropyl 4-(pyrimidine-5-yl)-phenyl
1163 3-fluoropropyl 5-isopropyl sulfenyl benzene-2-base
1164 3-fluoropropyl 2-chlorothiophene-5-base
1165 3-fluoropropyl 2,5-dichloro-thiophene-4-base
1166 3-fluoropropyl 2,3-dichloro-thiophene-5-base
1167 3-fluoropropyl The chloro-3-nitrothiophene-5-of 2-base
Numbering R 1 Ar
1168 3-fluoropropyl 2-(phenyl sulfonyl)-thiophene-5-base
1169 3-fluoropropyl 2-(pyridine-2-yl) thiophene-5-base
1170 3-fluoropropyl 2-(5-(trifluoromethyl) isoxazole-3-base)-thiophene-5-base
1171 3-fluoropropyl 2-(2-methylthiazol-4-yl)-thiophene-5-base
1172 3-fluoropropyl 1-methyl isophthalic acid H-imidazol-4 yl
1173 3-fluoropropyl 1,2-dimethyl-1H-imidazol-4 yl
1174 3-fluoropropyl 3,5-dimethyl isoxazole-4-base
1175 3-fluoropropyl Thiazol-2-yl
1176 3-fluoropropyl 4-methylthiazol-2-base
1177 3-fluoropropyl 4-sec.-propyl thiazol-2-yl
1178 3-fluoropropyl 4-trifluoromethyl thiazole-2-base
1179 3-fluoropropyl 5-methylthiazol-2-base
1180 3-fluoropropyl 5-sec.-propyl thiazol-2-yl
1181 3-fluoropropyl 5-trifluoromethyl thiazole-2-base
1182 3-fluoropropyl 2,4-dimethylthiazole-5-base
1183 3-fluoropropyl 2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-base
1184 3-fluoropropyl 4H-[1,2,4] triazole-3-base
1185 3-fluoropropyl 5-methyl-4H-[1,2,4] triazole-3-base
1186 3-fluoropropyl 4-methyl-4H-[1,2,4] triazole-3-base
1187 3-fluoropropyl 5-sec.-propyl-4H-[1,2,4] triazole-3-base
1188 3-fluoropropyl 5-trifluoromethyl-4H-[1,2,4] triazole-3-base
1189 3-fluoropropyl 4,5-dimethyl-4H-[1,2,4] triazole-3-base
1190 3-fluoropropyl 5-isopropyl-4-methyl-4H-[1,2,4] triazole-3-base
1191 3-fluoropropyl 5-trifluoromethyl-4-methyl-4H-[1,2,4] triazole-3-base
1192 3-fluoropropyl [1,3,4] thiadiazoles-2-base
1193 3-fluoropropyl 5-methyl-[1,3,4] thiadiazoles-2-base
1194 3-fluoropropyl 5-sec.-propyl-[1,3,4] thiadiazoles-2-base
1195 3-fluoropropyl 5-trifluoromethyl-[1,3,4] thiadiazoles-2-base
1196 3-fluoropropyl The bromo-2-chloropyridine-5-of 3-base
1197 3-fluoropropyl 2-(4-morpholino)-pyridine-5-base
Numbering R 1 Ar
1198 3-fluoropropyl 2-phenoxypyridines-5-base
1199 3-fluoropropyl (2-sec.-propyl)-pyrimidine-5-base
1200 3-fluoropropyl (5-sec.-propyl)-pyrimidine-2-base
1201 3-fluoropropyl 8-quinolyl
1202 3-fluoropropyl 5-isoquinolyl
1203 3-fluoropropyl 2-(trifluoroacetyl group)-1,2,3,4-tetrahydroisoquinoline-7-base
1204 3-fluoropropyl The chloro-3-methylbenzene thiophthene-2-of 5-base
1205 3-fluoropropyl 3,4-dihydro-4-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazinyl
1206 3-fluoropropyl Benzothiazol-6-yl
1207 3-fluoropropyl Benzo [2,1,3] oxadiazole-4-bases
1208 3-fluoropropyl 5-chlorobenzene is [2,1,3] oxadiazole-4-bases also
1209 3-fluoropropyl 7-chlorobenzene is [2,1,3] oxadiazole-4-bases also
1210 3-fluoropropyl Benzo [2,1,3] thiadiazoles-4-base
1211 2-fluoro ethyl 4-aminomethyl phenyl
1212 2-fluoro ethyl 4-ethylphenyl
1213 2-fluoro ethyl 4-propyl group phenyl
1214 2-fluoro ethyl 4-isopropyl phenyl
1215 2-fluoro ethyl 4-secondary butyl phenenyl
1216 2-fluoro ethyl 4-isobutyl phenenyl
1217 2-fluoro ethyl 4-(1,1-dimethyl propyl)-phenyl
1218 2-fluoro ethyl 4-ethenylphenyl
1219 2-fluoro ethyl 4-pseudoallyl phenyl
1220 2-fluoro ethyl 4-fluorophenyl
1221 2-fluoro ethyl 4-chloro-phenyl-
1222 2-fluoro ethyl 4-bromophenyl
1223 2-fluoro ethyl 4-(methyl fluoride) phenyl
1224 2-fluoro ethyl 3-(methyl fluoride) phenyl
1225 2-fluoro ethyl 2-(methyl fluoride) phenyl
1226 2-fluoro ethyl 4-(difluoromethyl) phenyl
1227 2-fluoro ethyl 3-(difluoromethyl) phenyl
Numbering R 1 Ar
1228 2-fluoro ethyl 2-(difluoromethyl) phenyl
1229 2-fluoro ethyl 4-(trifluoromethyl) phenyl
1230 2-fluoro ethyl 3-(trifluoromethyl) phenyl
1231 2-fluoro ethyl 2-(trifluoromethyl) phenyl
1232 2-fluoro ethyl 4-(1-fluoro ethyl)-phenyl
1233 2-fluoro ethyl 4-((S)-1-fluoro ethyl)-phenyl
1234 2-fluoro ethyl 4-((R)-1-fluoro ethyl)-phenyl
1235 2-fluoro ethyl 4-(2-fluoro ethyl)-phenyl
1236 2-fluoro ethyl 4-(1,1-, bis-fluoro ethyls)-phenyl
1237 2-fluoro ethyl 4-(2,2-, bis-fluoro ethyls)-phenyl
1238 2-fluoro ethyl 4-(2,2,2-trifluoroethyl)-phenyl
1239 2-fluoro ethyl 4-(3-fluoropropyl)-phenyl
1240 2-fluoro ethyl 4-(2-fluoropropyl)-phenyl
1241 2-fluoro ethyl 4-((S)-2-fluoropropyl)-phenyl
1242 2-fluoro ethyl 4-((R)-2-fluoropropyl)-phenyl
1243 2-fluoro ethyl 4-(3,3-, bis-fluoropropyls)-phenyl
1244 2-fluoro ethyl 4-(3,3,3-trifluoro propyl)-phenyl
1245 2-fluoro ethyl 4-(the fluoro-1-methylethyl of 1-)-phenyl
1246 2-fluoro ethyl 4-(the fluoro-1-methylethyl of 2-)-phenyl
1247 2-fluoro ethyl 4-(the fluoro-1-methylethyl of (S)-2-)-phenyl
1248 2-fluoro ethyl 4-(the fluoro-1-methylethyl of (R)-2-)-phenyl
1249 2-fluoro ethyl 4-(the fluoro-1-methylethyl of 2,2-bis-)-phenyl
1250 2-fluoro ethyl 4-((S)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
1251 2-fluoro ethyl 4-((R)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
1252 2-fluoro ethyl 4-(the fluoro-1-methylethyl of 2,2,2-tri-)-phenyl
1253 2-fluoro ethyl 4-((S)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
1254 2-fluoro ethyl 4-((R)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
1255 2-fluoro ethyl 4-(the fluoro-1-methyl fluoride of 2-ethyl)-phenyl
1256 2-fluoro ethyl 4-(1-difluoromethyl-2,2-bis-fluoro ethyls)-phenyl
1257 2-fluoro ethyl 4-(1,1-dimethyl-2-fluoro ethyl)-phenyl
Numbering R 1 Ar
1258 2-fluoro ethyl 4-p-methoxy-phenyl
1259 2-fluoro ethyl 4-ethoxyl phenenyl
1260 2-fluoro ethyl 4-propoxy-phenyl
1261 2-fluoro ethyl 4-isopropyl phenyl
1262 2-fluoro ethyl 4-butoxy phenyl
1263 2-fluoro ethyl 4-(fluorine methoxyl group)-phenyl
1264 2-fluoro ethyl 4-(difluoro-methoxy)-phenyl
1265 2-fluoro ethyl 4-(trifluoromethoxy)-phenyl
1266 2-fluoro ethyl 3-(trifluoromethoxy)-phenyl
1267 2-fluoro ethyl 4-(2-fluorine oxyethyl group)-phenyl
1268 2-fluoro ethyl 4-(2,2-difluoroethoxy)-phenyl
1269 2-fluoro ethyl 4-(2,2,2-trifluoro ethoxy)-phenyl
1270 2-fluoro ethyl 4-(1,1,2,2-tetrafluoro oxyethyl group)-phenyl
1271 2-fluoro ethyl 4-cyclopropyl phenyl
1272 2-fluoro ethyl 4-cyclobutyl phenyl
1273 2-fluoro ethyl 4-cyclopentyl phenyl
1274 2-fluoro ethyl 4-(2,2-difluoro cyclopropyl)-phenyl
1275 2-fluoro ethyl 3,4-difluorophenyl
1276 2-fluoro ethyl 4-bromine-3-fluorophenyl
1277 2-fluoro ethyl The bromo-2-fluorophenyl of 4-
1278 2-fluoro ethyl 4-is bromo-2,5-difluorophenyl
1279 2-fluoro ethyl The fluoro-4-isopropyl phenyl of 2-
1280 2-fluoro ethyl The fluoro-4-isopropyl phenyl of 3-
1281 2-fluoro ethyl 4-(1-hydroxyl-1-methylethyl)-phenyl
1282 2-fluoro ethyl 4-(2-hydroxy-2-methyl propyl group)-phenyl
1283 2-fluoro ethyl 4-acetylphenyl
1284 2-fluoro ethyl 4-carboxyl phenyl
1285 2-fluoro ethyl 4-cyano-phenyl
1286 2-fluoro ethyl 4-hydroxy phenyl
1287 2-fluoro ethyl 4-(O-benzyl)-phenyl
Numbering R 1 Ar
1288 2-fluoro ethyl 4-(2-methoxy ethoxy)-phenyl
1289 2-fluoro ethyl 4-(CH 2-N(CH 3) 2)-phenyl
1290 2-fluoro ethyl 4-(NH-CO-NH 2)-phenyl
1291 2-fluoro ethyl 4-(methylthio group)-phenyl
1292 2-fluoro ethyl 4-(fluorine methylthio group)-phenyl
1293 2-fluoro ethyl 4-(difluoro methylthio group)-phenyl
1294 2-fluoro ethyl 4-(trifluoromethylthio)-phenyl
1295 2-fluoro ethyl 4-(methyl sulphonyl)-phenyl
1296 2-fluoro ethyl 4-(N-methoxyl group-N-methyl-amino)-phenyl
1297 2-fluoro ethyl 4-(methoxyl group is amino)-phenyl
1298 2-fluoro ethyl 4-(oxyethyl group is amino)-phenyl
1299 2-fluoro ethyl 4-(N-methylamino oxygen base)-phenyl
1300 2-fluoro ethyl 4-(N, N-dimethylamino oxygen base)-phenyl
1301 2-fluoro ethyl 4-(azetidine-1-yl)-phenyl
1302 2-fluoro ethyl 4-(2-methyl azetidine-1-yl)-phenyl
1303 2-fluoro ethyl 4-((S)-2-methyl azetidine-1-yl)-phenyl
1304 2-fluoro ethyl 4-((R)-2-methyl azetidine-1-yl)-phenyl
1305 2-fluoro ethyl 4-(3-fluorine azetidine-1-yl)-phenyl
1306 2-fluoro ethyl 4-(3-methoxyl group azetidine-1-yl)-phenyl
1307 2-fluoro ethyl 4-(3-hydroxy azetidine-1-yl)-phenyl
1308 2-fluoro ethyl 4-(pyrrolidin-1-yl)-phenyl
1309 2-fluoro ethyl 4-(pyrrolidin-2-yl)-phenyl
1310 2-fluoro ethyl 4-((S)-pyrrolidin-2-yl)-phenyl
1311 2-fluoro ethyl 4-((R)-pyrrolidin-2-yl)-phenyl
1312 2-fluoro ethyl 4-(pyrrolidin-3-yl)-phenyl
1313 2-fluoro ethyl 4-((S)-pyrrolidin-3-yl)-phenyl
1314 2-fluoro ethyl 4-((R)-pyrrolidin-3-yl)-phenyl
1315 2-fluoro ethyl 4-(2-fluoropyrrolidine-1-yl)-phenyl
1316 2-fluoro ethyl 4-((S)-2-fluoropyrrolidine-1-yl)-phenyl
1317 2-fluoro ethyl 4-((R)-2-fluoropyrrolidine-1-yl)-phenyl
Numbering R 1 Ar
1318 2-fluoro ethyl 4-(3-fluoropyrrolidine-1-yl)-phenyl
1319 2-fluoro ethyl 4-((S)-3-fluoropyrrolidine-1-yl)-phenyl
1320 2-fluoro ethyl 4-((R)-3-fluoropyrrolidine-1-yl)-phenyl
1321 2-fluoro ethyl 4-(2,2-difluoro pyrrolidin-1-yl)-phenyl
1322 2-fluoro ethyl 4-(3,3-difluoro pyrrolidin-1-yl)-phenyl
1323 2-fluoro ethyl 4-(2-methylpyrrolidin-1-yl)-phenyl
1324 2-fluoro ethyl 4-((S)-2-methylpyrrolidin-1-yl)-phenyl
1325 2-fluoro ethyl 4-((R)-2-methylpyrrolidin-1-yl)-phenyl
1326 2-fluoro ethyl 4-(3-methylpyrrolidin-1-yl)-phenyl
1327 2-fluoro ethyl 4-((S)-3-methylpyrrolidin-1-yl)-phenyl
1328 2-fluoro ethyl 4-((R)-3-methylpyrrolidin-1-yl)-phenyl
1329 2-fluoro ethyl 4-(1-methylpyrrolidin-2-yl)-phenyl
1330 2-fluoro ethyl 4-((S)-1-methylpyrrolidin-2-yl)-phenyl
1331 2-fluoro ethyl 4-((R)-1-methylpyrrolidin-2-yl)-phenyl
1332 2-fluoro ethyl 4-(1-methylpyrrolidin-3-yl)-phenyl
1333 2-fluoro ethyl 4-((S)-1-methylpyrrolidin-3-yl)-phenyl
1334 2-fluoro ethyl 4-((R)-1-methylpyrrolidin-3-yl)-phenyl
1335 2-fluoro ethyl 4-(2,2-dimethyl pyrrolidine-1-yl)-phenyl
1336 2-fluoro ethyl 4-(3,3-dimethyl pyrrolidine-1-yl)-phenyl
1337 2-fluoro ethyl 4-(2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1338 2-fluoro ethyl 4-((S)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1339 2-fluoro ethyl 4-((R)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1340 2-fluoro ethyl 4-(3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1341 2-fluoro ethyl 4-((S)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1342 2-fluoro ethyl 4-((R)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1343 2-fluoro ethyl 4-(2-oxo-pyrrolidine-1-yl)-phenyl
1344 2-fluoro ethyl 4-(2-oxo-oxazolidines-3-yl)-phenyl
1345 2-fluoro ethyl 4-(piperidin-1-yl)-phenyl
1346 2-fluoro ethyl 4-(pipecoline-1-yl)-phenyl
1347 2-fluoro ethyl 4-((S)-pipecoline-1-yl)-phenyl
Numbering R 1 Ar
1348 2-fluoro ethyl 4-((R)-pipecoline-1-yl)-phenyl
1349 2-fluoro ethyl 4-(piperazine-1-yl)-phenyl
1350 2-fluoro ethyl 4-(4-methylpiperazine-1-yl)-phenyl
1351 2-fluoro ethyl 4-(morpholine-4-yl)-phenyl
1352 2-fluoro ethyl 4-(thiomorpholine-4-yl)-phenyl
1353 2-fluoro ethyl 4-(1-oxo-thiomorpholine-4-yl)-phenyl
1354 2-fluoro ethyl 4-(1,1-dioxo-thiomorpholine-4-yl)-phenyl
1355 2-fluoro ethyl 4-(pyrroles-1-yl)-phenyl
1356 2-fluoro ethyl 4-(pyrroles-2-yl)-phenyl
1357 2-fluoro ethyl 4-(pyrroles-3-yl)-phenyl
1358 2-fluoro ethyl 4-(1-methylpyrrole-2-yl)-phenyl
1359 2-fluoro ethyl 4-(1-methylpyrrole-3-yl)-phenyl
1360 2-fluoro ethyl 4-(furans-2-yl)-phenyl
1361 2-fluoro ethyl 4-(furans-3-yl)-phenyl
1362 2-fluoro ethyl 4-(thiophene-2-yl)-phenyl
1363 2-fluoro ethyl 4-(thiene-3-yl-)-phenyl
1364 2-fluoro ethyl 4-(5-propyl group thiophene-2-yl)-phenyl
1365 2-fluoro ethyl 4-(pyrazol-1-yl)-phenyl
1366 2-fluoro ethyl 4-(pyrazole-3-yl)-phenyl
1367 2-fluoro ethyl 4-(pyrazoles-4-yl)-phenyl
1368 2-fluoro ethyl 4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl
1369 2-fluoro ethyl 4-(1-ethyl-1H-pyrazoles-4-yl)-phenyl
1370 2-fluoro ethyl 4-(1-methyl isophthalic acid H-pyrazoles-5-yl)-phenyl
1371 2-fluoro ethyl 4-(1H-imidazoles-2-yl)-phenyl
1372 2-fluoro ethyl 4-(imidazoles-1-yl)-phenyl
1373 2-fluoro ethyl 4-(1-Methylimidazole-2-yl)-phenyl
1374 2-fluoro ethyl 4-(oxazole-2-yl)-phenyl
1375 2-fluoro ethyl 4-(oxazole-4-yl)-phenyl
1376 2-fluoro ethyl 4-(oxazole-5-yl)-phenyl
1377 2-fluoro ethyl 4-(isoxazole-3-base)-phenyl
Numbering R 1 Ar
1378 2-fluoro ethyl 4-(isoxazole-4-base)-phenyl
1379 2-fluoro ethyl 4-(isoxazole-5-base)-phenyl
1380 2-fluoro ethyl 4-([1,2,3]-triazol-1-yl)-phenyl
1381 2-fluoro ethyl 4-([1,2,4]-triazol-1-yl)-phenyl
1382 2-fluoro ethyl 4-([1,2,3]-triazole-2-yl)-phenyl
1383 2-fluoro ethyl 4-(4H-[1,2,4]-triazole-3-yl)-phenyl
1384 2-fluoro ethyl 4-([1,2,4]-triazole-4-yl)-phenyl
1385 2-fluoro ethyl 4-(2H-[1,2,3]-triazole-4-yl)-phenyl
1386 2-fluoro ethyl 4-(4-methyl-4H-[1,2,4]-triazole-3-yl)-phenyl
1387 2-fluoro ethyl 4-(2-methyl-2H-[1,2,3]-triazole-4-yl)-phenyl
1388 2-fluoro ethyl 4-([1,3,4]-oxadiazoles-2-yl)-phenyl
1389 2-fluoro ethyl 4-([1,2,4]-oxadiazoles-3-yl)-phenyl
1390 2-fluoro ethyl 4-([1,2,4]-oxadiazoles-5-yl)-phenyl
1391 2-fluoro ethyl 4-([1,2,3]-oxadiazoles-4-yl)-phenyl
1392 2-fluoro ethyl 4-([1,2,3]-oxadiazoles-5-yl)-phenyl
1393 2-fluoro ethyl 4-([1,2,3]-thiadiazoles-4-yl)-phenyl
1394 2-fluoro ethyl 4-(1H-TETRAZOLE-5-yl)-phenyl
1395 2-fluoro ethyl 4-(tetrazolium-1-yl)-phenyl
1396 2-fluoro ethyl 4-(2-methyl-2H-tetrazolium-5-yl)-phenyl
1397 2-fluoro ethyl 4-(1-methyl isophthalic acid H-tetrazolium-5-yl)-phenyl
1398 2-fluoro ethyl 4-furazan-3-base-phenyl
1399 2-fluoro ethyl 4-(pyridine-2-yl)-phenyl
1400 2-fluoro ethyl 4-(pyridin-3-yl)-phenyl
1401 2-fluoro ethyl 4-(pyridin-4-yl)-phenyl
1402 2-fluoro ethyl 4-(pyrimidine-2-base)-phenyl
1403 2-fluoro ethyl 4-(pyrimidine-4-yl)-phenyl
1404 2-fluoro ethyl 4-(pyrimidine-5-yl)-phenyl
1405 2-fluoro ethyl 5-isopropyl sulfenyl benzene-2-base
1406 2-fluoro ethyl 2-chlorothiophene-5-base
1407 2-fluoro ethyl 2,5-dichloro-thiophene-4-base
Numbering R 1 Ar
1408 2-fluoro ethyl 2,3-dichloro-thiophene-5-base
1409 2-fluoro ethyl The chloro-3-nitrothiophene-5-of 2-base
1410 2-fluoro ethyl 2-(phenyl sulfonyl)-thiophene-5-base
1411 2-fluoro ethyl 2-(pyridine-2-yl) thiophene-5-base
1412 2-fluoro ethyl 2-(5-(trifluoromethyl) isoxazole-3-base)-thiophene-5-base
1413 2-fluoro ethyl 2-(2-methylthiazol-4-yl)-thiophene-5-base
1414 2-fluoro ethyl 1-methyl isophthalic acid H-imidazol-4 yl
1415 2-fluoro ethyl 1,2-dimethyl-1H-imidazol-4 yl
1416 2-fluoro ethyl 3,5-dimethyl isoxazole-4-base
1417 2-fluoro ethyl Thiazol-2-yl
1418 2-fluoro ethyl 4-methylthiazol-2-base
1419 2-fluoro ethyl 4-sec.-propyl thiazol-2-yl
1420 2-fluoro ethyl 4-trifluoromethyl thiazole-2-base
1421 2-fluoro ethyl 5-methylthiazol-2-base
1422 2-fluoro ethyl 5-sec.-propyl thiazol-2-yl
1423 2-fluoro ethyl 5-trifluoromethyl thiazole-2-base
1424 2-fluoro ethyl 2,4-dimethylthiazole-5-base
1425 2-fluoro ethyl 2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-base
1426 2-fluoro ethyl 4H-[1,2,4] triazole-3-base
1427 2-fluoro ethyl 5-methyl-4H-[1,2,4] triazole-3-base
1428 2-fluoro ethyl 4-methyl-4H-[1,2,4] triazole-3-base
1429 2-fluoro ethyl 5-sec.-propyl-4H-[1,2,4] triazole-3-base
1430 2-fluoro ethyl 5-trifluoromethyl-4H-[1,2,4] triazole-3-base
1431 2-fluoro ethyl 4,5-dimethyl-4H-[1,2,4] triazole-3-base
1432 2-fluoro ethyl 5-isopropyl-4-methyl-4H-[1,2,4] triazole-3-base
1433 2-fluoro ethyl 5-trifluoromethyl-4-methyl-4H-[1,2,4] triazole-3-base
1434 2-fluoro ethyl [1,3,4] thiadiazoles-2-base
1435 2-fluoro ethyl 5-methyl-[1,3,4] thiadiazoles-2-base
1436 2-fluoro ethyl 5-sec.-propyl-[1,3,4] thiadiazoles-2-base
1437 2-fluoro ethyl 5-trifluoromethyl-[1,3,4] thiadiazoles-2-base
Numbering R 1 Ar
1438 2-fluoro ethyl The bromo-2-chloropyridine-5-of 3-base
1439 2-fluoro ethyl 2-(4-morpholino)-pyridine-5-base
1440 2-fluoro ethyl 2-phenoxypyridines-5-base
1441 2-fluoro ethyl (2-sec.-propyl)-pyrimidine-5-base
1442 2-fluoro ethyl (5-sec.-propyl)-pyrimidine-2-base
1443 2-fluoro ethyl 8-quinolyl
1444 2-fluoro ethyl 5-isoquinolyl
1445 2-fluoro ethyl 2-(trifluoroacetyl group)-1,2,3,4-tetrahydroisoquinoline-7-base
1446 2-fluoro ethyl The chloro-3-methylbenzene thiophthene-2-of 5-base
1447 2-fluoro ethyl 3,4-dihydro-4-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazinyl
1448 2-fluoro ethyl Benzothiazol-6-yl
1449 2-fluoro ethyl Benzo [2,1,3] oxadiazole-4-bases
1450 2-fluoro ethyl 5-chlorobenzene is [2,1,3] oxadiazole-4-bases also
1451 2-fluoro ethyl 7-chlorobenzene is [2,1,3] oxadiazole-4-bases also
1452 2-fluoro ethyl Benzo [2,1,3] thiadiazoles-4-base
1453 Cyclopropyl methyl 4-aminomethyl phenyl
1454 Cyclopropyl methyl 4-ethylphenyl
1455 Cyclopropyl methyl 4-propyl group phenyl
1456 Cyclopropyl methyl 4-isopropyl phenyl
1457 Cyclopropyl methyl 4-secondary butyl phenenyl
1458 Cyclopropyl methyl 4-isobutyl phenenyl
1459 Cyclopropyl methyl 4-(1,1-dimethyl propyl)-phenyl
1460 Cyclopropyl methyl 4-ethenylphenyl
1461 Cyclopropyl methyl 4-pseudoallyl phenyl
1462 Cyclopropyl methyl 4-fluorophenyl
1463 Cyclopropyl methyl 4-chloro-phenyl-
1464 Cyclopropyl methyl 4-bromophenyl
1465 Cyclopropyl methyl 4-(methyl fluoride) phenyl
1466 Cyclopropyl methyl 3-(methyl fluoride) phenyl
1467 Cyclopropyl methyl 2-(methyl fluoride) phenyl
Numbering R 1 Ar
1468 Cyclopropyl methyl 4-(difluoromethyl) phenyl
1469 Cyclopropyl methyl 3-(difluoromethyl) phenyl
1470 Cyclopropyl methyl 2-(difluoromethyl) phenyl
1471 Cyclopropyl methyl 4-(trifluoromethyl) phenyl
1472 Cyclopropyl methyl 3-(trifluoromethyl) phenyl
1473 Cyclopropyl methyl 2-(trifluoromethyl) phenyl
1474 Cyclopropyl methyl 4-(1-fluoro ethyl)-phenyl
1475 Cyclopropyl methyl 4-((S)-1-fluoro ethyl)-phenyl
1476 Cyclopropyl methyl 4-((R)-1-fluoro ethyl)-phenyl
1477 Cyclopropyl methyl 4-(2-fluoro ethyl)-phenyl
1478 Cyclopropyl methyl 4-(1,1-, bis-fluoro ethyls)-phenyl
1479 Cyclopropyl methyl 4-(2,2-, bis-fluoro ethyls)-phenyl
1480 Cyclopropyl methyl 4-(2,2,2-trifluoroethyl)-phenyl
1481 Cyclopropyl methyl 4-(3-fluoropropyl)-phenyl
1482 Cyclopropyl methyl 4-(2-fluoropropyl)-phenyl
1483 Cyclopropyl methyl 4-((S)-2-fluoropropyl)-phenyl
1484 Cyclopropyl methyl 4-((R)-2-fluoropropyl)-phenyl
1485 Cyclopropyl methyl 4-(3,3-, bis-fluoropropyls)-phenyl
1486 Cyclopropyl methyl 4-(3,3,3-trifluoro propyl)-phenyl
1487 Cyclopropyl methyl 4-(the fluoro-1-methylethyl of 1-)-phenyl
1488 Cyclopropyl methyl 4-(the fluoro-1-methylethyl of 2-)-phenyl
1489 Cyclopropyl methyl 4-(the fluoro-1-methylethyl of (S)-2-)-phenyl
1490 Cyclopropyl methyl 4-(the fluoro-1-methylethyl of (R)-2-)-phenyl
1491 Cyclopropyl methyl 4-(the fluoro-1-methylethyl of 2,2-bis-)-phenyl
1492 Cyclopropyl methyl 4-((S)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
1493 Cyclopropyl methyl 4-((R)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
1494 Cyclopropyl methyl 4-(the fluoro-1-methylethyl of 2,2,2-tri-)-phenyl
1495 Cyclopropyl methyl 4-((S)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
1496 Cyclopropyl methyl 4-((R)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
1497 Cyclopropyl methyl 4-(the fluoro-1-methyl fluoride of 2-ethyl)-phenyl
Numbering R 1 Ar
1498 Cyclopropyl methyl 4-(1-difluoromethyl-2,2-bis-fluoro ethyls)-phenyl
1499 Cyclopropyl methyl 4-(1,1-dimethyl-2-fluoro ethyl)-phenyl
1500 Cyclopropyl methyl 4-p-methoxy-phenyl
1501 Cyclopropyl methyl 4-ethoxyl phenenyl
1502 Cyclopropyl methyl 4-propoxy-phenyl
1503 Cyclopropyl methyl 4-isopropyl phenyl
1504 Cyclopropyl methyl 4-butoxy phenyl
1505 Cyclopropyl methyl 4-(fluorine methoxyl group)-phenyl
1506 Cyclopropyl methyl 4-(difluoro-methoxy)-phenyl
1507 Cyclopropyl methyl 4-(trifluoromethoxy)-phenyl
1508 Cyclopropyl methyl 3-(trifluoromethoxy)-phenyl
1509 Cyclopropyl methyl 4-(2-fluorine oxyethyl group)-phenyl
1510 Cyclopropyl methyl 4-(2,2-difluoroethoxy)-phenyl
1511 Cyclopropyl methyl 4-(2,2,2-trifluoro ethoxy)-phenyl
1512 Cyclopropyl methyl 4-(1,1,2,2-tetrafluoro oxyethyl group)-phenyl
1513 Cyclopropyl methyl 4-cyclopropyl phenyl
1514 Cyclopropyl methyl 4-cyclobutyl phenyl
1515 Cyclopropyl methyl 4-cyclopentyl phenyl
1516 Cyclopropyl methyl 4-(2,2-difluoro cyclopropyl)-phenyl
1517 Cyclopropyl methyl 3,4-difluorophenyl
1518 Cyclopropyl methyl 4-bromine-3-fluorophenyl
1519 Cyclopropyl methyl The bromo-2-fluorophenyl of 4-
1520 Cyclopropyl methyl 4-is bromo-2,5-difluorophenyl
1521 Cyclopropyl methyl The fluoro-4-isopropyl phenyl of 2-
1522 Cyclopropyl methyl The fluoro-4-isopropyl phenyl of 3-
1523 Cyclopropyl methyl 4-(1-hydroxyl-1-methylethyl)-phenyl
1524 Cyclopropyl methyl 4-(2-hydroxy-2-methyl propyl group)-phenyl
1525 Cyclopropyl methyl 4-acetylphenyl
1526 Cyclopropyl methyl 4-carboxyl phenyl
1527 Cyclopropyl methyl 4-cyano-phenyl
Numbering R 1 Ar
1528 Cyclopropyl methyl 4-hydroxy phenyl
1529 Cyclopropyl methyl 4-(O-benzyl)-phenyl
1530 Cyclopropyl methyl 4-(2-methoxy ethoxy)-phenyl
1531 Cyclopropyl methyl 4-(CH 2-N(CH 3) 2)-phenyl
1532 Cyclopropyl methyl 4-(NH-CO-NH 2)-phenyl
1533 Cyclopropyl methyl 4-(methylthio group)-phenyl
1534 Cyclopropyl methyl 4-(fluorine methylthio group)-phenyl
1535 Cyclopropyl methyl 4-(difluoro methylthio group)-phenyl
1536 Cyclopropyl methyl 4-(trifluoromethylthio)-phenyl
1537 Cyclopropyl methyl 4-(methyl sulphonyl)-phenyl
1538 Cyclopropyl methyl 4-(N-methoxyl group-N-methyl-amino)-phenyl
1539 Cyclopropyl methyl 4-(methoxyl group is amino)-phenyl
1540 Cyclopropyl methyl 4-(oxyethyl group is amino)-phenyl
1541 Cyclopropyl methyl 4-(N-methylamino oxygen base)-phenyl
1542 Cyclopropyl methyl 4-(N, N-dimethylamino oxygen base)-phenyl
1543 Cyclopropyl methyl 4-(azetidine-1-yl)-phenyl
1544 Cyclopropyl methyl 4-(2-methyl azetidine-1-yl)-phenyl
1545 Cyclopropyl methyl 4-((S)-2-methyl azetidine-1-yl)-phenyl
1546 Cyclopropyl methyl 4-((R)-2-methyl azetidine-1-yl)-phenyl
1547 Cyclopropyl methyl 4-(3-fluorine azetidine-1-yl)-phenyl
1548 Cyclopropyl methyl 4-(3-methoxyl group azetidine-1-yl)-phenyl
1549 Cyclopropyl methyl 4-(3-hydroxy azetidine-1-yl)-phenyl
1550 Cyclopropyl methyl 4-(pyrrolidin-1-yl)-phenyl
1551 Cyclopropyl methyl 4-(pyrrolidin-2-yl)-phenyl
1552 Cyclopropyl methyl 4-((S)-pyrrolidin-2-yl)-phenyl
1553 Cyclopropyl methyl 4-((R)-pyrrolidin-2-yl)-phenyl
1554 Cyclopropyl methyl 4-(pyrrolidin-3-yl)-phenyl
1555 Cyclopropyl methyl 4-((S)-pyrrolidin-3-yl)-phenyl
1556 Cyclopropyl methyl 4-((R)-pyrrolidin-3-yl)-phenyl
1557 Cyclopropyl methyl 4-(2-fluoropyrrolidine-1-yl)-phenyl
Numbering R 1 Ar
1558 Cyclopropyl methyl 4-((S)-2-fluoropyrrolidine-1-yl)-phenyl
1559 Cyclopropyl methyl 4-((R)-2-fluoropyrrolidine-1-yl)-phenyl
1560 Cyclopropyl methyl 4-(3-fluoropyrrolidine-1-yl)-phenyl
1561 Cyclopropyl methyl 4-((S)-3-fluoropyrrolidine-1-yl)-phenyl
1562 Cyclopropyl methyl 4-((R)-3-fluoropyrrolidine-1-yl)-phenyl
1563 Cyclopropyl methyl 4-(2,2-difluoro pyrrolidin-1-yl)-phenyl
1564 Cyclopropyl methyl 4-(3,3-difluoro pyrrolidin-1-yl)-phenyl
1565 Cyclopropyl methyl 4-(2-methylpyrrolidin-1-yl)-phenyl
1566 Cyclopropyl methyl 4-((S)-2-methylpyrrolidin-1-yl)-phenyl
1567 Cyclopropyl methyl 4-((R)-2-methylpyrrolidin-1-yl)-phenyl
1568 Cyclopropyl methyl 4-(3-methylpyrrolidin-1-yl)-phenyl
1569 Cyclopropyl methyl 4-((S)-3-methylpyrrolidin-1-yl)-phenyl
1570 Cyclopropyl methyl 4-((R)-3-methylpyrrolidin-1-yl)-phenyl
1571 Cyclopropyl methyl 4-(1-methylpyrrolidin-2-yl)-phenyl
1572 Cyclopropyl methyl 4-((S)-1-methylpyrrolidin-2-yl)-phenyl
1573 Cyclopropyl methyl 4-((R)-1-methylpyrrolidin-2-yl)-phenyl
1574 Cyclopropyl methyl 4-(1-methylpyrrolidin-3-yl)-phenyl
1575 Cyclopropyl methyl 4-((S)-1-methylpyrrolidin-3-yl)-phenyl
1576 Cyclopropyl methyl 4-((R)-1-methylpyrrolidin-3-yl)-phenyl
1577 Cyclopropyl methyl 4-(2,2-dimethyl pyrrolidine-1-yl)-phenyl
1578 Cyclopropyl methyl 4-(3,3-dimethyl pyrrolidine-1-yl)-phenyl
1579 Cyclopropyl methyl 4-(2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1580 Cyclopropyl methyl 4-((S)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1581 Cyclopropyl methyl 4-((R)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1582 Cyclopropyl methyl 4-(3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1583 Cyclopropyl methyl 4-((S)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1584 Cyclopropyl methyl 4-((R)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1585 Cyclopropyl methyl 4-(2-oxo-pyrrolidine-1-yl)-phenyl
1586 Cyclopropyl methyl 4-(2-oxo-oxazolidines-3-yl)-phenyl
1587 Cyclopropyl methyl 4-(piperidin-1-yl)-phenyl
Numbering R 1 Ar
1588 Cyclopropyl methyl 4-(pipecoline-1-yl)-phenyl
1589 Cyclopropyl methyl 4-((S)-pipecoline-1-yl)-phenyl
1590 Cyclopropyl methyl 4-((R)-pipecoline-1-yl)-phenyl
1591 Cyclopropyl methyl 4-(piperazine-1-yl)-phenyl
1592 Cyclopropyl methyl 4-(4-methylpiperazine-1-yl)-phenyl
1593 Cyclopropyl methyl 4-(morpholine-4-yl)-phenyl
1594 Cyclopropyl methyl 4-(thiomorpholine-4-yl)-phenyl
1595 Cyclopropyl methyl 4-(1-oxo-thiomorpholine-4-yl)-phenyl
1596 Cyclopropyl methyl 4-(1,1-dioxo-thiomorpholine-4-yl)-phenyl
1597 Cyclopropyl methyl 4-(pyrroles-1-yl)-phenyl
1598 Cyclopropyl methyl 4-(pyrroles-2-yl)-phenyl
1599 Cyclopropyl methyl 4-(pyrroles-3-yl)-phenyl
1600 Cyclopropyl methyl 4-(1-methylpyrrole-2-yl)-phenyl
1601 Cyclopropyl methyl 4-(1-methylpyrrole-3-yl)-phenyl
1602 Cyclopropyl methyl 4-(furans-2-yl)-phenyl
1603 Cyclopropyl methyl 4-(furans-3-yl)-phenyl
1604 Cyclopropyl methyl 4-(thiophene-2-yl)-phenyl
1605 Cyclopropyl methyl 4-(thiene-3-yl-)-phenyl
1606 Cyclopropyl methyl 4-(5-propyl group thiophene-2-yl)-phenyl
1607 Cyclopropyl methyl 4-(pyrazol-1-yl)-phenyl
1608 Cyclopropyl methyl 4-(pyrazole-3-yl)-phenyl
1609 Cyclopropyl methyl 4-(pyrazoles-4-yl)-phenyl
1610 Cyclopropyl methyl 4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl
1611 Cyclopropyl methyl 4-(1-ethyl-1H-pyrazoles-4-yl)-phenyl
1612 Cyclopropyl methyl 4-(1-methyl isophthalic acid H-pyrazoles-5-yl)-phenyl
1613 Cyclopropyl methyl 4-(1H-imidazoles-2-yl)-phenyl
1614 Cyclopropyl methyl 4-(imidazoles-1-yl)-phenyl
1615 Cyclopropyl methyl 4-(1-Methylimidazole-2-yl)-phenyl
1616 Cyclopropyl methyl 4-(oxazole-2-yl)-phenyl
1617 Cyclopropyl methyl 4-(oxazole-4-yl)-phenyl
Numbering R 1 Ar
1618 Cyclopropyl methyl 4-(oxazole-5-yl)-phenyl
1619 Cyclopropyl methyl 4-(isoxazole-3-base)-phenyl
1620 Cyclopropyl methyl 4-(isoxazole-4-base)-phenyl
1621 Cyclopropyl methyl 4-(isoxazole-5-base)-phenyl
1622 Cyclopropyl methyl 4-([1,2,3]-triazol-1-yl)-phenyl
1623 Cyclopropyl methyl 4-([1,2,4]-triazol-1-yl)-phenyl
1624 Cyclopropyl methyl 4-([1,2,3]-triazole-2-yl)-phenyl
1625 Cyclopropyl methyl 4-(4H-[1,2,4]-triazole-3-yl)-phenyl
1626 Cyclopropyl methyl 4-([1,2,4]-triazole-4-yl)-phenyl
1627 Cyclopropyl methyl 4-(2H-[1,2,3]-triazole-4-yl)-phenyl
1628 Cyclopropyl methyl 4-(4-methyl-4H-[1,2,4]-triazole-3-yl)-phenyl
1629 Cyclopropyl methyl 4-(2-methyl-2H-[1,2,3]-triazole-4-yl)-phenyl
1630 Cyclopropyl methyl 4-([1,3,4]-oxadiazoles-2-yl)-phenyl
1631 Cyclopropyl methyl 4-([1,2,4]-oxadiazoles-3-yl)-phenyl
1632 Cyclopropyl methyl 4-([1,2,4]-oxadiazoles-5-yl)-phenyl
1633 Cyclopropyl methyl 4-([1,2,3]-oxadiazoles-4-yl)-phenyl
1634 Cyclopropyl methyl 4-([1,2,3]-oxadiazoles-5-yl)-phenyl
1635 Cyclopropyl methyl 4-([1,2,3]-thiadiazoles-4-yl)-phenyl
1636 Cyclopropyl methyl 4-(1H-TETRAZOLE-5-yl)-phenyl
1637 Cyclopropyl methyl 4-(tetrazolium-1-yl)-phenyl
1638 Cyclopropyl methyl 4-(2-methyl-2H-tetrazolium-5-yl)-phenyl
1639 Cyclopropyl methyl 4-(1-methyl isophthalic acid H-tetrazolium-5-yl)-phenyl
1640 Cyclopropyl methyl 4-furazan-3-base-phenyl
1641 Cyclopropyl methyl 4-(pyridine-2-yl)-phenyl
1642 Cyclopropyl methyl 4-(pyridin-3-yl)-phenyl
1643 Cyclopropyl methyl 4-(pyridin-4-yl)-phenyl
1644 Cyclopropyl methyl 4-(pyrimidine-2-base)-phenyl
1645 Cyclopropyl methyl 4-(pyrimidine-4-yl)-phenyl
1646 Cyclopropyl methyl 4-(pyrimidine-5-yl)-phenyl
1647 Cyclopropyl methyl 5-isopropyl sulfenyl benzene-2-base
Numbering R 1 Ar
1648 Cyclopropyl methyl 2-chlorothiophene-5-base
1649 Cyclopropyl methyl 2,5-dichloro-thiophene-4-base
1650 Cyclopropyl methyl 2,3-dichloro-thiophene-5-base
1651 Cyclopropyl methyl The chloro-3-nitrothiophene-5-of 2-base
1652 Cyclopropyl methyl 2-(phenyl sulfonyl)-thiophene-5-base
1653 Cyclopropyl methyl 2-(pyridine-2-yl) thiophene-5-base
1654 Cyclopropyl methyl 2-(5-(trifluoromethyl) isoxazole-3-base)-thiophene-5-base
1655 Cyclopropyl methyl 2-(2-methylthiazol-4-yl)-thiophene-5-base
1656 Cyclopropyl methyl 1-methyl isophthalic acid H-imidazol-4 yl
1657 Cyclopropyl methyl 1,2-dimethyl-1H-imidazol-4 yl
1658 Cyclopropyl methyl 3,5-dimethyl isoxazole-4-base
1659 Cyclopropyl methyl Thiazol-2-yl
1660 Cyclopropyl methyl 4-methylthiazol-2-base
1661 Cyclopropyl methyl 4-sec.-propyl thiazol-2-yl
1662 Cyclopropyl methyl 4-trifluoromethyl thiazole-2-base
1663 Cyclopropyl methyl 5-methylthiazol-2-base
1664 Cyclopropyl methyl 5-sec.-propyl thiazol-2-yl
1665 Cyclopropyl methyl 5-trifluoromethyl thiazole-2-base
1666 Cyclopropyl methyl 2,4-dimethylthiazole-5-base
1667 Cyclopropyl methyl 2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-base
1668 Cyclopropyl methyl 4H-[1,2,4] triazole-3-base
1669 Cyclopropyl methyl 5-methyl-4H-[1,2,4] triazole-3-base
1670 Cyclopropyl methyl 4-methyl-4H-[1,2,4] triazole-3-base
1671 Cyclopropyl methyl 5-sec.-propyl-4H-[1,2,4] triazole-3-base
1672 Cyclopropyl methyl 5-trifluoromethyl-4H-[1,2,4] triazole-3-base
1673 Cyclopropyl methyl 4,5-dimethyl-4H-[1,2,4] triazole-3-base
1674 Cyclopropyl methyl 5-isopropyl-4-methyl-4H-[1,2,4] triazole-3-base
1675 Cyclopropyl methyl 5-trifluoromethyl-4-methyl-4H-[1,2,4] triazole-3-base
1676 Cyclopropyl methyl [1,3,4] thiadiazoles-2-base
1677 Cyclopropyl methyl 5-methyl-[1,3,4] thiadiazoles-2-base
Numbering R 1 Ar
1678 Cyclopropyl methyl 5-sec.-propyl-[1,3,4] thiadiazoles-2-base
1679 Cyclopropyl methyl 5-trifluoromethyl-[1,3,4] thiadiazoles-2-base
1680 Cyclopropyl methyl The bromo-2-chloropyridine-5-of 3-base
1681 Cyclopropyl methyl 2-(4-morpholino)-pyridine-5-base
1682 Cyclopropyl methyl 2-phenoxypyridines-5-base
1683 Cyclopropyl methyl (2-sec.-propyl)-pyrimidine-5-base
1684 Cyclopropyl methyl (5-sec.-propyl)-pyrimidine-2-base
1685 Cyclopropyl methyl 8-quinolyl
1686 Cyclopropyl methyl 5-isoquinolyl
1687 Cyclopropyl methyl 2-(trifluoroacetyl group)-1,2,3,4-tetrahydroisoquinoline-7-base
1688 Cyclopropyl methyl The chloro-3-methylbenzene thiophthene-2-of 5-base
1689 Cyclopropyl methyl 3,4-dihydro-4-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazinyl
1690 Cyclopropyl methyl Benzothiazol-6-yl
1691 Cyclopropyl methyl Benzo [2,1,3] oxadiazole-4-bases
1692 Cyclopropyl methyl 5-chlorobenzene is [2,1,3] oxadiazole-4-bases also
1693 Cyclopropyl methyl 7-chlorobenzene is [2,1,3] oxadiazole-4-bases also
1694 Cyclopropyl methyl Benzo [2,1,3] thiadiazoles-4-base
1695 Allyl group 4-aminomethyl phenyl
1696 Allyl group 4-ethylphenyl
1697 Allyl group 4-propyl group phenyl
1698 Allyl group 4-isopropyl phenyl
1699 Allyl group 4-secondary butyl phenenyl
1700 Allyl group 4-isobutyl phenenyl
1701 Allyl group 4-(1,1-dimethyl propyl)-phenyl
1702 Allyl group 4-ethenylphenyl
1703 Allyl group 4-pseudoallyl phenyl
1704 Allyl group 4-fluorophenyl
1705 Allyl group 4-chloro-phenyl-
1706 Allyl group 4-bromophenyl
1707 Allyl group 4-(methyl fluoride) phenyl
Numbering R 1 Ar
1708 Allyl group 3-(methyl fluoride) phenyl
1709 Allyl group 2-(methyl fluoride) phenyl
1710 Allyl group 4-(difluoromethyl) phenyl
1711 Allyl group 3-(difluoromethyl) phenyl
1712 Allyl group 2-(difluoromethyl) phenyl
1713 Allyl group 4-(trifluoromethyl) phenyl
1714 Allyl group 3-(trifluoromethyl) phenyl
1715 Allyl group 2-(trifluoromethyl) phenyl
1716 Allyl group 4-(1-fluoro ethyl)-phenyl
1717 Allyl group 4-((S)-1-fluoro ethyl)-phenyl
1718 Allyl group 4-((R)-1-fluoro ethyl)-phenyl
1719 Allyl group 4-(2-fluoro ethyl)-phenyl
1720 Allyl group 4-(1,1-, bis-fluoro ethyls)-phenyl
1721 Allyl group 4-(2,2-, bis-fluoro ethyls)-phenyl
1722 Allyl group 4-(2,2,2-trifluoroethyl)-phenyl
1723 Allyl group 4-(3-fluoropropyl)-phenyl
1724 Allyl group 4-(2-fluoropropyl)-phenyl
1725 Allyl group 4-((S)-2-fluoropropyl)-phenyl
1726 Allyl group 4-((R)-2-fluoropropyl)-phenyl
1727 Allyl group 4-(3,3-, bis-fluoropropyls)-phenyl
1728 Allyl group 4-(3,3,3-trifluoro propyl)-phenyl
1729 Allyl group 4-(the fluoro-1-methylethyl of 1-)-phenyl
1730 Allyl group 4-(the fluoro-1-methylethyl of 2-)-phenyl
1731 Allyl group 4-(the fluoro-1-methylethyl of (S)-2-)-phenyl
1732 Allyl group 4-(the fluoro-1-methylethyl of (R)-2-)-phenyl
1733 Allyl group 4-(the fluoro-1-methylethyl of 2,2-bis-)-phenyl
1734 Allyl group 4-((S)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
1735 Allyl group 4-((R)-2, the fluoro-1-methylethyl of 2-bis-)-phenyl
1736 Allyl group 4-(the fluoro-1-methylethyl of 2,2,2-tri-)-phenyl
1737 Allyl group 4-((S)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
Numbering R 1 Ar
1738 Allyl group 4-((R)-2,2, the fluoro-1-methylethyl of 2-tri-)-phenyl
1739 Allyl group 4-(the fluoro-1-methyl fluoride of 2-ethyl)-phenyl
1740 Allyl group 4-(1-difluoromethyl-2,2-bis-fluoro ethyls)-phenyl
1741 Allyl group 4-(1,1-dimethyl-2-fluoro ethyl)-phenyl
1742 Allyl group 4-p-methoxy-phenyl
1743 Allyl group 4-ethoxyl phenenyl
1744 Allyl group 4-propoxy-phenyl
1745 Allyl group 4-isopropyl phenyl
1746 Allyl group 4-butoxy phenyl
1747 Allyl group 4-(fluorine methoxyl group)-phenyl
1748 Allyl group 4-(difluoro-methoxy)-phenyl
1749 Allyl group 4-(trifluoromethoxy)-phenyl
1750 Allyl group 3-(trifluoromethoxy)-phenyl
1751 Allyl group 4-(2-fluorine oxyethyl group)-phenyl
1752 Allyl group 4-(2,2-difluoroethoxy)-phenyl
1753 Allyl group 4-(2,2,2-trifluoro ethoxy)-phenyl
1754 Allyl group 4-(1,1,2,2-tetrafluoro oxyethyl group)-phenyl
1755 Allyl group 4-cyclopropyl phenyl
1756 Allyl group 4-cyclobutyl phenyl
1757 Allyl group 4-cyclopentyl phenyl
1758 Allyl group 4-(2,2-difluoro cyclopropyl)-phenyl
1759 Allyl group 3,4-difluorophenyl
1760 Allyl group 4-bromine-3-fluorophenyl
1761 Allyl group The bromo-2-fluorophenyl of 4-
1762 Allyl group 4-is bromo-2,5-difluorophenyl
1763 Allyl group The fluoro-4-isopropyl phenyl of 2-
1764 Allyl group The fluoro-4-isopropyl phenyl of 3-
1765 Allyl group 4-(1-hydroxyl-1-methylethyl)-phenyl
1766 Allyl group 4-(2-hydroxy-2-methyl propyl group)-phenyl
1767 Allyl group 4-acetylphenyl
Numbering R 1 Ar
1768 Allyl group 4-carboxyl phenyl
1769 Allyl group 4-cyano-phenyl
1770 Allyl group 4-hydroxy phenyl
1771 Allyl group 4-(O-benzyl)-phenyl
1772 Allyl group 4-(2-methoxy ethoxy)-phenyl
1773 Allyl group 4-(CH 2-N(CH 3) 2)-phenyl
1774 Allyl group 4-(NH-CO-NH 2)-phenyl
1775 Allyl group 4-(methylthio group)-phenyl
1776 Allyl group 4-(fluorine methylthio group)-phenyl
1777 Allyl group 4-(difluoro methylthio group)-phenyl
1778 Allyl group 4-(trifluoromethylthio)-phenyl
1779 Allyl group 4-(methyl sulphonyl)-phenyl
1780 Allyl group 4-(N-methoxyl group-N-methyl-amino)-phenyl
1781 Allyl group 4-(methoxyl group is amino)-phenyl
1782 Allyl group 4-(oxyethyl group is amino)-phenyl
1783 Allyl group 4-(N-methylamino oxygen base)-phenyl
1784 Allyl group 4-(N, N-dimethylamino oxygen base)-phenyl
1785 Allyl group 4-(azetidine-1-yl)-phenyl
1786 Allyl group 4-(2-methyl azetidine-1-yl)-phenyl
1787 Allyl group 4-((S)-2-methyl azetidine-1-yl)-phenyl
1788 Allyl group 4-((R)-2-methyl azetidine-1-yl)-phenyl
1789 Allyl group 4-(3-fluorine azetidine-1-yl)-phenyl
1790 Allyl group 4-(3-methoxyl group azetidine-1-yl)-phenyl
1791 Allyl group 4-(3-hydroxy azetidine-1-yl)-phenyl
1792 Allyl group 4-(pyrrolidin-1-yl)-phenyl
1793 Allyl group 4-(pyrrolidin-2-yl)-phenyl
1794 Allyl group 4-((S)-pyrrolidin-2-yl)-phenyl
1795 Allyl group 4-((R)-pyrrolidin-2-yl)-phenyl
1796 Allyl group 4-(pyrrolidin-3-yl)-phenyl
1797 Allyl group 4-((S)-pyrrolidin-3-yl)-phenyl
Numbering R 1 Ar
1798 Allyl group 4-((R)-pyrrolidin-3-yl)-phenyl
1799 Allyl group 4-(2-fluoropyrrolidine-1-yl)-phenyl
1800 Allyl group 4-((S)-2-fluoropyrrolidine-1-yl)-phenyl
1801 Allyl group 4-((R)-2-fluoropyrrolidine-1-yl)-phenyl
1802 Allyl group 4-(3-fluoropyrrolidine-1-yl)-phenyl
1803 Allyl group 4-((S)-3-fluoropyrrolidine-1-yl)-phenyl
1804 Allyl group 4-((R)-3-fluoropyrrolidine-1-yl)-phenyl
1805 Allyl group 4-(2,2-difluoro pyrrolidin-1-yl)-phenyl
1806 Allyl group 4-(3,3-difluoro pyrrolidin-1-yl)-phenyl
1807 Allyl group 4-(2-methylpyrrolidin-1-yl)-phenyl
1808 Allyl group 4-((S)-2-methylpyrrolidin-1-yl)-phenyl
1809 Allyl group 4-((R)-2-methylpyrrolidin-1-yl)-phenyl
1810 Allyl group 4-(3-methylpyrrolidin-1-yl)-phenyl
1811 Allyl group 4-((S)-3-methylpyrrolidin-1-yl)-phenyl
1812 Allyl group 4-((R)-3-methylpyrrolidin-1-yl)-phenyl
1813 Allyl group 4-(1-methylpyrrolidin-2-yl)-phenyl
1814 Allyl group 4-((S)-1-methylpyrrolidin-2-yl)-phenyl
1815 Allyl group 4-((R)-1-methylpyrrolidin-2-yl)-phenyl
1816 Allyl group 4-(1-methylpyrrolidin-3-yl)-phenyl
1817 Allyl group 4-((S)-1-methylpyrrolidin-3-yl)-phenyl
1818 Allyl group 4-((R)-1-methylpyrrolidin-3-yl)-phenyl
1819 Allyl group 4-(2,2-dimethyl pyrrolidine-1-yl)-phenyl
1820 Allyl group 4-(3,3-dimethyl pyrrolidine-1-yl)-phenyl
1821 Allyl group 4-(2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1822 Allyl group 4-((S)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1823 Allyl group 4-((R)-2-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1824 Allyl group 4-(3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1825 Allyl group 4-((S)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1826 Allyl group 4-((R)-3-trifluoromethyl pyrpole alkane-1-yl)-phenyl
1827 Allyl group 4-(2-oxo-pyrrolidine-1-yl)-phenyl
Numbering R 1 Ar
1828 Allyl group 4-(2-oxo-oxazolidines-3-yl)-phenyl
1829 Allyl group 4-(piperidin-1-yl)-phenyl
1830 Allyl group 4-(pipecoline-1-yl)-phenyl
1831 Allyl group 4-((S)-pipecoline-1-yl)-phenyl
1832 Allyl group 4-((R)-pipecoline-1-yl)-phenyl
1833 Allyl group 4-(piperazine-1-yl)-phenyl
1834 Allyl group 4-(4-methylpiperazine-1-yl)-phenyl
1835 Allyl group 4-(morpholine-4-yl)-phenyl
1836 Allyl group 4-(thiomorpholine-4-yl)-phenyl
1837 Allyl group 4-(1-oxo-thiomorpholine-4-yl)-phenyl
1838 Allyl group 4-(1,1-dioxo-thiomorpholine-4-yl)-phenyl
1839 Allyl group 4-(pyrroles-1-yl)-phenyl
1840 Allyl group 4-(pyrroles-2-yl)-phenyl
1841 Allyl group 4-(pyrroles-3-yl)-phenyl
1842 Allyl group 4-(1-methylpyrrole-2-yl)-phenyl
1843 Allyl group 4-(1-methylpyrrole-3-yl)-phenyl
1844 Allyl group 4-(furans-2-yl)-phenyl
1845 Allyl group 4-(furans-3-yl)-phenyl
1846 Allyl group 4-(thiophene-2-yl)-phenyl
1847 Allyl group 4-(thiene-3-yl-)-phenyl
1848 Allyl group 4-(5-propyl group thiophene-2-yl)-phenyl
1849 Allyl group 4-(pyrazol-1-yl)-phenyl
1850 Allyl group 4-(pyrazole-3-yl)-phenyl
1851 Allyl group 4-(pyrazoles-4-yl)-phenyl
1852 Allyl group 4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl
1853 Allyl group 4-(1-ethyl-1H-pyrazoles-4-yl)-phenyl
1854 Allyl group 4-(1-methyl isophthalic acid H-pyrazoles-5-yl)-phenyl
1855 Allyl group 4-(1H-imidazoles-2-yl)-phenyl
1856 Allyl group 4-(imidazoles-1-yl)-phenyl
1857 Allyl group 4-(1-Methylimidazole-2-yl)-phenyl
Numbering R 1 Ar
1858 Allyl group 4-(oxazole-2-yl)-phenyl
1859 Allyl group 4-(oxazole-4-yl)-phenyl
1860 Allyl group 4-(oxazole-5-yl)-phenyl
1861 Allyl group 4-(isoxazole-3-base)-phenyl
1862 Allyl group 4-(isoxazole-4-base)-phenyl
1863 Allyl group 4-(isoxazole-5-base)-phenyl
1864 Allyl group 4-([1,2,3]-triazol-1-yl)-phenyl
1865 Allyl group 4-([1,2,4]-triazol-1-yl)-phenyl
1866 Allyl group 4-([1,2,3]-triazole-2-yl)-phenyl
1867 Allyl group 4-(4H-[1,2,4]-triazole-3-yl)-phenyl
1868 Allyl group 4-([1,2,4]-triazole-4-yl)-phenyl
1869 Allyl group 4-(2H-[1,2,3]-triazole-4-yl)-phenyl
1870 Allyl group 4-(4-methyl-4H-[1,2,4]-triazole-3-yl)-phenyl
1871 Allyl group 4-(2-methyl-2H-[1,2,3]-triazole-4-yl)-phenyl
1872 Allyl group 4-([1,3,4]-oxadiazoles-2-yl)-phenyl
1873 Allyl group 4-([1,2,4]-oxadiazoles-3-yl)-phenyl
1874 Allyl group 4-([1,2,4]-oxadiazoles-5-yl)-phenyl
1875 Allyl group 4-([1,2,3]-oxadiazoles-4-yl)-phenyl
1876 Allyl group 4-([1,2,3]-oxadiazoles-5-yl)-phenyl
1877 Allyl group 4-([1,2,3]-thiadiazoles-4-yl)-phenyl
1878 Allyl group 4-(1H-TETRAZOLE-5-yl)-phenyl
1879 Allyl group 4-(tetrazolium-1-yl)-phenyl
1880 Allyl group 4-(2-methyl-2H-tetrazolium-5-yl)-phenyl
1881 Allyl group 4-(1-methyl isophthalic acid H-tetrazolium-5-yl)-phenyl
1882 Allyl group 4-furazan-3-base-phenyl
1883 Allyl group 4-(pyridine-2-yl)-phenyl
1884 Allyl group 4-(pyridin-3-yl)-phenyl
1885 Allyl group 4-(pyridin-4-yl)-phenyl
1886 Allyl group 4-(pyrimidine-2-base)-phenyl
1887 Allyl group 4-(pyrimidine-4-yl)-phenyl
Numbering R 1 Ar
1888 Allyl group 4-(pyrimidine-5-yl)-phenyl
1889 Allyl group 5-isopropyl sulfenyl benzene-2-base
1890 Allyl group 2-chlorothiophene-5-base
1891 Allyl group 2,5-dichloro-thiophene-4-base
1892 Allyl group 2,3-dichloro-thiophene-5-base
1893 Allyl group The chloro-3-nitrothiophene-5-of 2-base
1894 Allyl group 2-(phenyl sulfonyl)-thiophene-5-base
1895 Allyl group 2-(pyridine-2-yl) thiophene-5-base
1896 Allyl group 2-(5-(trifluoromethyl) isoxazole-3-base)-thiophene-5-base
1897 Allyl group 2-(2-methylthiazol-4-yl)-thiophene-5-base
1898 Allyl group 1-methyl-IH-imidazol-4 yl
1899 Allyl group 1,2-dimethyl-1H-imidazol-4 yl
1900 Allyl group 3,5-dimethyl isoxazole-4-base
1901 Allyl group Thiazol-2-yl
1902 Allyl group 4-methylthiazol-2-base
1903 Allyl group 4-sec.-propyl thiazol-2-yl
1904 Allyl group 4-trifluoromethyl thiazole-2-base
1905 Allyl group 5-methylthiazol-2-base
1906 Allyl group 5-sec.-propyl thiazol-2-yl
1907 Allyl group 5-trifluoromethyl thiazole-2-base
1908 Allyl group 2,4-dimethylthiazole-5-base
1909 Allyl group 2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-base
1910 Allyl group 4H-[1,2,4] triazole-3-base
1911 Allyl group 5-methyl-4H-[1,2,4] triazole-3-base
1912 Allyl group 4-methyl-4H-[1,2,4] triazole-3-base
1913 Allyl group 5-sec.-propyl-4H-[1,2,4] triazole-3-base
1914 Allyl group 5-trifluoromethyl-4H-[1,2,4] triazole-3-base
1915 Allyl group 4,5-dimethyl-4H-[1,2,4] triazole-3-base
1916 Allyl group 5-isopropyl-4-methyl-4H-[1,2,4] triazole-3-base
1917 Allyl group 5-trifluoromethyl-4-methyl-4H-[1,2,4] triazole-3-base
Numbering R 1 Ar
1918 Allyl group [1,3,4] thiadiazoles-2-base
1919 Allyl group 5-methyl-[1,3,4] thiadiazoles-2-base
1920 Allyl group 5-sec.-propyl-[1,3,4] thiadiazoles-2-base
1921 Allyl group 5-trifluoromethyl-[1,3,4] thiadiazoles-2-base
1922 Allyl group The bromo-2-chloropyridine-5-of 3-base
1923 Allyl group 2-(4-morpholino)-pyridine-5-base
1924 Allyl group 2-phenoxypyridines-5-base
1925 Allyl group (2-sec.-propyl)-pyrimidine-5-base
1926 Allyl group (5-sec.-propyl)-pyrimidine-2-base
1927 Allyl group 8-quinolyl
1928 Allyl group 5-isoquinolyl
1929 Allyl group 2-(trifluoroacetyl group)-1,2,3,4-tetrahydroisoquinoline-7-base
1930 Allyl group The chloro-3-methylbenzene thiophthene-2-of 5-base
1931 Allyl group 3,4-dihydro-4-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazinyl
1932 Allyl group Benzothiazol-6-yl
1933 Allyl group Benzo [2,1,3] oxadiazole-4-bases
1934 Allyl group 5-chlorobenzene is [2,1,3] oxadiazole-4-bases also
1935 Allyl group 7-chlorobenzene is [2,1,3] oxadiazole-4-bases also
1936 Allyl group Benzo [2,1,3] thiadiazoles-4-base
1937 Allyl group 6-chlorine imidazo [2,1-b] thiazolyl
The compounds of this invention I can synthesize shown in route of synthesis A, B below and C.
Reaction scheme 1:
In reaction scheme 1, A, Ar, G, n, R 2and R 4as defined above.R ' is R 1or R 1precursor.
Approach A
In approach A, aminocompound (II-1) is reacted to generate sulphonamide (I-1) (E=NH) with suitable sulfonic acid.Suitable sulfonic acid is SULPHURYL CHLORIDE Ar-SO for example 2cl.According to the standard method in this area, sulfonylation preferably carries out under alkali exists.In the reaction that reaction scheme 1 is described in the above, sulfonylation is to carry out being usually used in respectively preparing under the reaction conditions of arylsulfonamide compounds or aromatic yl sulphonate, and described reaction conditions is described in for example J.March, Advanced Organic Chemistry, 3 rdversion, John Wiley & Sons, New York, 1985p.444ff and the document of wherein quoting, European J.Org.Chem.2002 (13), pp.2094-2108, Tetrahedron 2001,57 (27) pp.5885-5895, Bioorganic and Medicinal Chemistry Letters, 2000,10 (8), pp.835-838and Synthesis2000 (1), in pp.103-108.This reaction is carried out conventionally in inert solvent, described solvent is ether for example, for example ether, Di Iso Propyl Ether, methyl tertiary butyl ether or tetrahydrofuran (THF), hydrocarbon is methylene dichloride for example, aliphatic series or clicyclic hydrocarbon be pentane, hexane or hexanaphthene for example, or aromatic hydrocarbon such as toluene, dimethylbenzene, isopropyl benzene etc., or the mixture of above-mentioned solvent.With Cl-SO 2the reaction of-Ar is carried out conventionally under auxiliary alkali exists.Suitable alkali is mineral alkali, for example sodium carbonate or salt of wormwood, or sodium bicarbonate or saleratus, and organic bases trialkylamine triethylamine for example for example, or pyridine compounds such as pyridine, lutidine etc.A rear compound can play solvent simultaneously.Auxiliary alkali with at least equimolar amount use, is counted based on amine compound (II-1) conventionally.
Before sulfonation reaction, can be by group NH 2change into NR 5 'group, wherein R 5 'have about R 5implication beyond the dehydrogenation of defined (not showing in reaction scheme 1).
If gained sulphonamide (I '-1) R ' is not required radicals R 1, but its precursor can as shown belowly modify to obtain required substituent R to this compound 1.Precursor is such group, and it is easy to be removed and by required radicals R 1substitute, or can modify to generate R 1.Precursor can also be N-protected base.
If R ' is allyl group, can to obtain wherein R ', be the compound of hydrogen by allyl group cracking.Allylic cracking can realize like this: by compound (I '-1) [R '=allyl group] and allyl group trapping agent Thiosalicylic acid or 1 for example, 3-dimethyl barbituric acid is at palladium (0) compound of catalytic amount or the palladium compound that can form palladium (0) compound under reaction conditions palladium chloride for example, under tetrakis triphenylphosphine palladium (0) or three (dibenzalacetone) two palladiums (0) exist, advantageously with phosphine part for example triaryl phosphine as triphenylphosphine, trialkyl phosphine is as tributylphosphine, with cycloalkyl phosphine tricyclohexyl phosphine for example, associating use, and especially with phosphine inner complex part for example 2, 2 '-bis-(diphenylphosphino)-1, 1 '-dinaphthalene or 1, there is lower reaction in 4-bis-(diphenylphosphino) butane, this reaction is used known in the literature method (under existing at Thiosalicylic acid, to eliminate N-allyl group, referring to WO94/24088, about the elimination under existing at 1,3-dimethyl barbituric acid, referring to J.Am.Chem.Soc.2001,123 (28), pp.6801-6808 and J.Org.Chem2002,67 (11) pp.3718-3723).Or, the allylic cracking of N-can also be by under existing as three (triphenylphosphine) rhodium chloride (I) at rhodium compound, by known in the literature method, react to realize (referring to J.Chem.Soc., Perkin Transaction I:Organic andBio-Organic Chemistry1999 (21) pp.3089-3104 and TetrahedronAsymmetry1997,8 (20), pp.3387-3391).
If R ' is benzyl, can to obtain wherein R ', be the compound (I '-1) of H by this substituting group cracking.For this cracking, reaction conditions is known in the art.Typically, by Pd catalyzer, for example palladium on carbon or palladium hydroxide carry out hydrogenation under existing and remove benzyl.
R ' can also be protecting group.Protecting group can be removed to generate wherein R ' is the compound (I '-1) of H.Suitable protecting group is known in the art, and is for example selected from tertiary butyl oxygen base carbonyl (boc), benzyloxycarbonyl (Cbz), 9-fluorenyl methoxy carbonyl (Fmoc), trityl group (Trt) and oil of mirbane sulfinyl (Nps).Preferred protecting group is boc.Protecting group can be removed by currently known methods, for example with acid as haloid acid for example HCl or HBr or trifluoroacetic acid process the amine of protection, or by hydrogenation, optionally under the existence of Pd catalyzer, protecting group is removed in hydrogenation.
The gained compound that can be by R ' wherein then H can be by known alkylation mode and compound R 1-X reaction.In this compound, R 1c 1-C 4-alkyl, C 3-C 6-cycloalkyl, C 1-C 4-haloalkyl, C 1-C 4-alkoxy-C 1-C 4-alkyl or C 3-C 6-cycloalkyl-C 1-C 4-alkyl, and X be can nucleophilic displacement leavings group, such as halogen, trifluoro-acetate, alkyl sulfonic ester, aromatic yl sulphonate, alkyl sulfuric ester etc.Carry out the required reaction conditions of alkylation by fully open, for example, at Bioorganic and Medicinal Chemistry Lett.2002,12 (7), pp.2443-2446and also2002,12 (5), in pp.1917-1919.
In reduction amination meaning, alkylation can also by the compound of R '=H (I '-1) wherein react to carry out under reductive agent exists with suitable ketone or aldehyde, for example, for example be reacted under sodium borohydride, sodium cyanoborohydride or sodium triacetoxy borohydride existence at hydroborate.The required reaction conditions of reduction amination is carried out in those skilled in the art's understanding, for example, be recorded in Bioorganic and Medicinal Chemistry Lett.2002, and 12 (5), in pp.795-798and12 (7) pp.1269-1273.
When R ' is hydrogen, gained sulphonamide (I '-1) further can be reacted with carboxylic acid halides, to obtain wherein R 1c 1-c 3-the formula I compound of alkyl-carbonyl.Can be with diborane by the carbonyl reduction in these compounds, to obtain wherein R 1c 2-C 4the compound of Formula I of-alkyl.Carbonyl can also be reacted to obtain wherein R with fluorizating agent 1it is the Compound I of 1,1-fluoroalkyl.Acidylate and reduction can realize by standard method; described standard method is described in Jerry March; Advanced OrganicChemistry, 3rd ed.J.Wiley & Sons, New York1985; p.370and373 (acylation) and p.1099f. and the document of quoting in this publication (about acidylate also referring to Synth.Commun.1986; 16, p.267, about reducing also referring to J.Heterocycl.Chem.1979; 16, p.1525) in.
Approach B
In approach B, the compound (II-2) that bromine is replaced and suitable sulphonamide ArSO 2nHR 5reaction, obtains sulphonamide (I '-1).This reaction is generally carried out under activation condition, for example, under microwave condition, carry out.Pd, especially Pd (0), or Cu catalyzer also can be for coupling (referring to for example Org.Lett. 2000,2,1101; J.Am.Chem.Soc.2002,124,6043; Org.Lett.2003,5,4373; Tetrahedron Lett.2003,44,3385).The example of suitable Pd (0) catalyzer has tetrakis triphenylphosphine palladium (0) and Pd 2(dba) 3(three (dibenzalacetone)-bis-palladiums (0)), it is conventionally at three (replacement) phosphine, triaryl phosphine triphenylphosphine for example for example, trimethylphenyl phosphine or xantphos, there is lower use in three (ring) alkylphosphines for example tri-n-butyl phosphine, three (tertiary butyl) phosphine or three (cyclohexyl phosphine).In the time can not adopting corresponding SULPHURYL CHLORIDE, the method is useful especially.
Or, bromine substituent can substitute with amino substituting group, for example, by reacting to realize with benzophenone imine or with two (trimethyl silyl) Lithamide, this reaction is at palladium (0) compound under for example three (dibenzalacetone) two palladiums (0) exist, and at three (replacement) phosphine, for example triphenylphosphine or trimethylphenyl phosphine of triaryl phosphine for example, three (ring) alkylphosphines is tri-n-butyl phosphine for example, under three (tertiary butyl) phosphines or three (cyclohexyl phosphine) exist, preferably at alkali, for example under sodium hydride existence, carry out, this is to carry out (referring to for example J.Org.Chem. according to the method for describing in the literature, 68 (2993) pp8274-8276, J.Org.Chem.2000, 65, 2612).Then gained aminocompound can be carried out to the sulfonation reaction of approach A.
Approach C
In approach C, by compound (II-3) and sulfhydryl compound HS-Ar alkali for example sodium hydride or alcoholization sodium under existing, react or react with its an alkali metal salt, generate thus sulfide compound.Then thioether partial oxygen is changed into sulfone part, for example, by oxone, be oxidized, to generate sulfone (I '-2).
Substituent A r can be by the different SULPHURYL CHLORIDE of use or by changing with the substituting group of currently known methods modification cyclic group Ar afterwards at formation sulphonamide (I '-1).For example, according to Tetrahedron Asym.1999, the method for describing in 10,1831, can replace the bromine substituent of Ar with the pyrrolidyl of N-bonding.According to Stille coupling, the bromine substituent of Ar can be substituted with pseudoallyl, wherein that bromine compounds is for example reacted (referring to for example Tetrahedron under tetra-triphenylphosphine palladium (0) existence at suitable Pd coupling catalyst with alkenyl tributyl tin acid esters, 2003,59 (34), 6545and Bioorg.Med.Chem.1999,7 (5), 665).By known method for hydrogenation, pseudoallyl can be changed into sec.-propyl.
Formula (II) (II-1, II-2 and II-3) compound can as followsly synthesize.
1. synthetic compound (II-1)
Reaction scheme 2
In reaction scheme 2, A, G, n and R ' are as defined above.
Acid (III) is changed into its methyl esters (IV) and by standard technique, undertaken, for example, be described in JerryMarch, Advanced Organic Chemistry, John Wiley, 3 rdversion, p.348ff in.For example, acid is changed into corresponding carboxylic acid halides, for example, by by itself and SOCl 2these words are carried out in reaction.Then by reacting this acyl chlorides changed into ester with methyl alcohol.
Reduction in step (ii) is suitably being carried out for carboxylicesters being changed under the standard conditions of alcohol.Suitable reaction conditions and reductive agent are described in for example Jerry March, Advanced OrganicChemistry, John Wiley, 3 rdversion, p.1093ff in.Typical reductive agent is metal hydride and complex hydride.The example of suitable metal hydride comprises BH 3, 9-BBN, AlH 3and AlH (i-Bu) 2(DIBAL-H), suitably at double solvents under for example tetrahydrofuran (THF) and ether exist.Complex hydride is NaBH for example 4, LiAlH 4and LiAlH (OR) 3, wherein R is C 1-C 4-alkyl is methyl, ethyl, isobutyl-or the tertiary butyl for example.Preferred reductive agent is LiAlH 4.At double solvents, for example open chain and cyclic ether for example suitably carry out in tetrahydrofuran (THF), ether, dipropyl ether, Di Iso Propyl Ether, dibutyl ether and methyl butyl ether in reduction.Preferred solvent is tetrahydrofuran (THF).
In methylsulfonyl step (iii), alcohol functional group is changed into good leavings group.Methylsulfonyl carries out under standard conditions, for example, alcohol and methylsulfonyl chloride are carried out under alkali exists.Suitable alkali is alkylamine, for example diethylamine, triethylamine and ethyl diisopropyl amine.In this step, can introduce represent good leavings group other functional group such as trifluoro-acetate, other alkyl sulfonic ester, aromatic yl sulphonate such as toluenesulphonic acids only, alkyl sulfuric ester etc. replaces methylsulfonyl.
In cyclization step (iv), by compound (VI) or its suitable derivative and primary amine NH 2r ' reaction.When primary amine is liquid.It can also be used as solvent, without any need for other solvent.If amine be thickness or solid, this reaction is advantageously carried out in suitable solvent.
The reaction of step (v) is to carry out under the reaction conditions that is usually used in nitration reaction on aromatic group, and this reaction conditions is described in for example Jerry Ma rch, Advanced Organic Chemistry, JohnWiley, 3 rdversion, p.468ff, Tetrahedron1999,55 (33), pp.10243-10252, J.Med.Chem.1997,40 (22), pp.3679-3686 and Synthetic Communications, 1993,23 (5), in pp.591-599.For example, by compound (VII) and concentrated nitric acid or nitrate, for example saltpetre or SODIUMNITRATE are reacted under the vitriol oil exists.Products therefrom (VIII) can be different regional isomer form (for example, if A is phenyl or 6 yuan of heteroaryls, adjacent, or contraposition.When A is phenyl or 6 yuan of heteroaryls, contraposition-nitro-compound is preponderated conventionally.Yet, also can obtain some ortho position product, and metacompaund does not generate at all or only with negligible quantity, generates.By separated ortho position and contraposition product, wherein A be the aryl of Isosorbide-5-Nitrae-bonding or the formula I compound of heteroaryl and wherein A be that the Compound I of 1,2-bonding aryl or heteroaryl obtains by reaction path shown in reaction scheme 2.
In step (vi), the nitroreduction in (VIII) is become to NH 2group.Then, can be by NH 2groups converted one-tenth-NR 5 'group, wherein R 5 'have about R 5the implication that the dehydrogenation of defined is thought.The required reaction conditions of step (vi) is equivalent to the normal condition for aromatic nitro is reduced, this fully describes in the literature (referring to for example J.March, Advanced OrganicChemistry, 3rd ed., J.Wiley & Sons, New-York, 1985, p.1183 and the document wherein quoted).Reduction is for example carried out like this: by nitro-compound VII, for example iron, zinc or tin react under acid-reaction condition with metal, use nascent hydrogen reaction, or use complex hydride for example lithium aluminium hydride or hydroborate, preferably at the transistion metal compound of nickel or cobalt NiCl for example 2(P (phenyl) 3) 2, or CoCl 2under existence, (referring to people .Chem.Ind. (London) such as Ono, 1983p.480), or use NaBH 2s 3(referring to people .Can.J.Chem.49 such as Lalancette, 1971, p.2990), according to given reagent, can in essence or carry out these reduction in solvent or thinner.For example, or reduction can be carried out with hydrogen under transition-metal catalyst exists, and carries out under the catalyzer based on platinum, palladium, nickel, ruthenium or rhodium exists with hydrogen.Catalyzer can contain transition metal, transition metal is element form or complex chemical compound form, the salt of transition metal or oxide form, for modification activities, can use for example for example triphenylphosphine, tricyclohexyl phosphine or tri-n-butyl phosphine or phosphite of organic phosphine compound of conventional assistant ligand.Catalyzer is used with the amount of 0.001-1mol/mol nitro-compound conventionally, according to catalyst metal, calculates.In preferred scheme, reduction is with tin chloride (II), to be similar to Bioorganic and Medicinal Chemistry Letters, 2002,12 (15), pp.1917-1919and J.Med.Chem.2002,45 (21), the method for describing in PP.4679-4688 is carried out.Reacting preferably at inert organic solvents of VII and tin chloride (II), preferred alcohols is for example carried out in methyl alcohol, ethanol, Virahol or butanols.
For n wherein, be 1, and A is the compound ((I) is N-(pyrrolidin-3-yl)-phenyl-sulphonamide) of phenylene, and compound (III) is for example commercially available (S) or (R) phenylsuccinic acid or its racemic mixture in fact.By (S) from enantiomer-pure-or (R)-compound (III), can obtain pure (S)-or (R):
A) (S) isomer
In step (i), commercially available (S)-phenylsuccinic acid (II-S) is changed into methyl esters (III); Methyl esters is reduced into alcohol (IV), this alcohol is reacted with methylsulfonyl chloride.Use primary amine cyclization, generate Phenylpyrrolidine (VI), first that phenyl is nitrated, then nitroreduction is become to amido functional group, amido functional group is reacted with SULPHURYL CHLORIDE, generate required sulphonamide (I '-S).
(R) isomer
(R)-isomer can, according to similar approach, be obtained by commercially available (R)-phenylsuccinic acid (III-R):
C) isomer mixture
Compound I ' isomer mixture of-S and I '-R can be by starting to obtain from racemize III or from the mixture of III-S and III-R.
It will be appreciated by those skilled in the art that describe synthetic is also suitable for preparing compound (II) and prepares subsequently compound (I), wherein R in reaction scheme 2, R 3and R 4not H, for example, from the compound (III) of corresponding replacement.This is also applicable to the synthetic of enantiomer-pure (I), and it can be by starting to synthesize from corresponding enantiomorph (III).
2. synthetic compound (II-2)
Formula (II-2) compound can replace nitrated synthesizing by carry out halogenation in reaction scheme 2 steps (v).The halogenating reaction of aryl and heteroaryl is well-known standard method, and is described in for example JerryMarch, Advanced Organic Chemistry, John Wiley, 3 rdversion p.476ff in.
3. synthetic compound (II-3)
The synthetic standard reaction method that belongs to of these compounds, and can be undertaken by the aryl of methyl substituted aryl or heteroaryl compound is carried out to single halogenation.
4. specifically synthetic
4.1 wherein n be the synthetic of 5 compound (pyrrolidyl sulfone derivatives)
4.1.1
Reaction scheme 3:
In reaction scheme 3, A and R 3as defined above.
Pyrrolidine ring can also be by for example, by unstabilized azomethine inner salt and 1-alkenyl aryl or heteroaryl derivative (IX) (vinyl benzene, R 3=H) [3+2] dipole-ring addition obtains.The method general description is at J.Org.Chem1987, in 52,235.The precursor of inner salt, amine N (CH 2r b) (CH 2siMe 3) (CH 2oCH 3) (X) be commercially available or can be by NH 2(CH 2r b), Me 3siCH 2cl and HCHO are synthetic under methyl alcohol exists.
1-alkenyl-(mixing) aromatic substance (IX) can be for example synthetic like this: by halogeno-benzene for example bromobenzene and corresponding alkenyl tributyl tin acid esters for example vinyl or isobutenyl tributyl tin acid esters suitable Pd coupling catalyst for example tetra-triphenylphosphine palladium (0) under existing, carry out Stille coupling (referring to for example Tetrahedron, 2003, 59 (34), 6545and Bioorg.Med.Chem.1999, 7 (5), 665), for example, by selecting specific Stille isomer (cis-or trans-isobutenyl tributyl tin acid esters), optionally make corresponding cis-or trans alkyl phenyl tetramethyleneimine.
Or 1-alkenyl-(mixing) aromatic substance (IX) can be by aryl aldehyde and Wittig reagent PPh for example 3(R is H or C to=CHR 1-C 3-alkyl) Wittig reaction is synthesized.The condition of carrying out Wittig reaction is well-known in the art, and is described in for example Jerry March, AdvancedOrganic Chemistry, John Wiley, 3 rdversion, p.845ff in.
Advantageously, (IX also carries nitro or another halogenic substituent (X=NO to 1-(mixing) alkenyl-aromatic substance 2or halogen).In this case, reactions steps subsequently can be carried out as shown in approach A or B.If X=H first encircles A nitratedly as described in reaction scheme 2 steps (v), then carry out reaction scheme 2 steps (vi) and reaction scheme 1, approach A; Or can, by ring A halogenation, then carry out the method for approach B.
The group CH of precursor amine 2r bthe required radicals R that is advantageously equivalent to final Compound I 1or the group of cleavable benzyl for example, can be removed to obtain the unsubstituted tetramethyleneimine of N-.Then the latter can be carried out as mentioned above to functionalized (referring to approach A).
For A, be pyridylidene, synthetic for example Chem.Pharm.Bull., 1985,33, the 2762-66 of being described in of heteroaryl tetramethyleneimine; J.Heterocyclic Chemistry, 1996,1995-2005; J.Heterocyclic Chemistry, 2001,38,1039-1044; Tetrahedron Letters, 1992,33,44,6607-10; Heterocycles, in 1998,48,12,2535-2541.The synthetic for example Bioorg.Med.Chem.1999 that is described in of the thiophene of vinyl-replacement and thiazole, in 7 (5), 665.
4.1.2
Reaction scheme 4:
Phenylpyrrolidine can also make like this: by [3+2] azo cycloaddition (referring to for example Tetrahedron1996,52,59) of unstabilized azomethine inner salt and 1-alkynyl benzene (XII).Then gained pyrroline (XIII) or final product (I ') are hydrogenated to corresponding tetramethyleneimine (XI).If hydrogenation is to carry out under chirality condition, for example with chiral catalyst, carry out hydrogenation, can obtain the Phenylpyrrolidine compounds of enantiomer-pure.Chiral hydrogenation catalyst is well-known in the art.Being subsequently converted to required sulphonamide can carry out as described in approach A or B.
4.1.3
Or heteroaryl pyrrolidinyl compound can be made by heteroaryl halogenide, the crosslinking reaction that heteroaryl halogenide and organic zinc pyrrolidine compound are carried out to Pd mediation.Below in approach F, be described in more detail the method.In the method, heteroaryl halogenide advantageously carries nitro.In this case, can as described in approach A, change into required sulphonamide.Or heteroaryl halogen carries halogen atom.In this case, changing into required sulphonamide can realize as described in approach B.
4.1.4
Wherein n is that 1, G is CH 2, A is arylidene or the inferior heteroaryl of 1,3-bonding, and E is that the Compound I of NH can be made by 3-aminoaryl or heteroaryl tetramethyleneimine according to being similar to the method for preparing Isosorbide-5-Nitrae-bonding compound, and this tetramethyleneimine is reacted with suitable SULPHURYL CHLORIDE.Advantageously, for example benzyloxycarbonyl (cbz) and tert-butoxycarbonyl (boc) protect the N-atom of pyrrolidine ring to be used to protecting group based on urathane.This group can be used required substituent R by the following method 1replace: with acid salt acid treatment compound for example, remove thus acid groups, then as described in approach A, introduce required substituting group.
3-aminoaryl or heteroaryl-tetramethyleneimine can be reacted and be made by Heck, wherein the tetramethyleneimine of protection are reacted under typical Heck condition with the iodo-3-oil of mirbane of 1-.According to the method for describing in reaction scheme 2, the two keys of pyrroline are carried out to catalytic hydrogenation and by nitroreduction, obtain required product.
4.2 synthetic N-(azetidine-3-yl)-sulphonamide
Wherein n is that 0 Compound I (azetidine compounds) can as described belowly be synthesized:
Reaction scheme 5:
In reaction scheme 5, Ar and R1 are as defined above.X and Y are CH or N independently of one another.
From 1-diphenyl-methyl-aza-cyclobutane-3-alcohol, (Tetrahedron 2002,58 to carry out the amine deprotection of Pd-mediation, 9865-9870), carbamate forms and halogenation subsequently, (Tetrahedron 1987,43,2203-2212 for the intermediate that generation experience Zn inserts; J.Org.Chem.1988,53,2390-2392).Thus obtained organic zinc compound can be reacted with suitable 2-halo-nitro-ring to (Synlett 1998,4,379-380; J.Am.Chem.Soc.2003,125,12527-12530), generate nitro-aryl-azetidine core.If use 2-halo-halo-ring, also can realize direct coupling (Org.Lett.2000,2,1101-1104 between aryl-azetidine halogenide and suitable sulphonamide; J.Am.Chem.Soc.2002,124,6043-6048; Org. Lett.2003,5,4373-4376; Tetrahedron Lett.2003,44,3385-3386).Amine can be regenerated by the cracking of carbamate (for example, for Boc carbamate, adopting trifluoroacetic acid), subsequently by changing into acid amides with suitable acyl chloride reaction.Can for example, by tin chloride or catalytic hydrogenation (Pd-C) nitroreduction be become to amine, then by for example reacting and change into required sulphonamide with suitable SULPHURYL CHLORIDE under pyridine existence at alkali.Finally by hydrogenation by reduction of amide, obtain final compound.
Certainly, to be also applicable to wherein with (mixing) aromatic ring of azetidinyl bonding be for example compound of thienyl of 5-unit heteroaryl in this reaction.
4.3 synthetic N-(piperidines-3-yl)-sulphonamide
Except above-mentioned synthetic (approach A, B and C), wherein n is 2, and E is NR 5the Compound I of (piperidines-3-base sulphonamide) can start to make by the 3-aryl from commercially available or 3-heteroaryl piperidine.Then these initial compounds can be changed into amino-replacement or halide derivative, carry out afterwards the synthetic of approach A or B.
One of ordinary skill in the art will readily recognize that compound of Formula I can also be by the compound of similar by functional group's acquisition that is mutually converted.Particularly, by the following method can be by the radicals R of N-bonding abe incorporated in formula I compound: by corresponding halogenated compound, wherein carry halogen atom, particularly bromine or iodine atom replaces R aformula I compound and primary amine or secondary amine under alkali exists, preferably also under palladium catalyst exists, according to Buchwald-Hartwig, react.
Except as otherwise noted, above-mentioned reaction generally, in solvent, is carried out in the boiling temperature of room temperature-solvent for use.Or, can use microwave that the required activation energy of reaction is incorporated in reaction mixture, wherein microwave has been proved to be valuable, particularly for the reaction by transition metal-catalyzed (about using the reaction of microwave, referring to Tetrahedron 2001,57, p.9199ff.p.9225ff. and in due form, ＂ Microwaves in Organic Synthesis ＂, Andr é Loupy (Ed.), Wiley-VCH2002.
SULPHURYL CHLORIDE Cl-SO 2-Ar can be commercially available, or can make according to standard synthetic method.Contain fluoro radicals R asULPHURYL CHLORIDE can make by different route of synthesis, for example, for example, by suitable hydroxyl or oxo precursor (are carried to the Compound C l-SO of the group that hydroxyl or oxo replace 2-Ar) with fluorination reagent for example DAST (three fluoridize diethylamino sulphur), morpholine-DAST, deoxo-fluor (three fluoridize two (2-methoxy ethyl) amino sulphur), Ishikawa ' s reagent (N, N-diethyl-(1,1,2,3,3,3-hexafluoro propyl group) amine reacts to make; Journal of Fluorine Chemistry, 1989,43,371-377).More generally, the hydroxyl that carries the group of hydroxyl replacement rather than the aromatic substance of chlorosulfonyl is changed into leavings group, then by fluoride ion replacement (J.Org.Chem., 1994,59,2898-22901 for leavings group; Tetrahedron Letters, 1998,7305-6; J.Org.Chem., 1998,63,9587-9589, Synthesis, 1987,920-21)).Then, with chlorsulfonic acid, directly carry out chlorosulfonylation (Heterocycles, 2001,55,9,1789-1803; J.Org.Chem., 2000,65,1399-1406) or carry out two step method, first prepare sulfonic acid, then with for example chlorsulfonic acid, phosphorus pentachloride, convert it into SULPHURYL CHLORIDE (Eur.J.Med.Chem., 2002,36,809-828) etc., obtain required SULPHURYL CHLORIDE (Tetrahedron Letters, 1991,33,507787-7788)).SULPHURYL CHLORIDE can also make like this: under acidic conditions, use Sodium Nitrite by suitable amine precursor Ar-NH 2diazotization, and in acetic acid, react (reaction scheme (iii) with sulfurous gas; J.Org.Chem., 1960,25,1824-26); By suitable heteroaryl-mercaptan HS-Ar or heteroaryl-benzyl-thioether C 6h 5-CH 2chlorine for-S-Ar (Synthesis, 1998,36-38; J.Am.Chem.Soc., 1950,74,4890-92; ) be direct oxidation into corresponding SULPHURYL CHLORIDE.These other compounds are known in the art or can make by standard method.For example, sulfydryl-pyrimidine or pyrimidyl-benzyl thioether precursor can for example make (Chemische Berichte, 1960,1208-11 according to the method in document; Chemische Berichte, 1960,95,230-235; Collection Czechoslow.Chem.Comm., 1959,24,1667-1671; Austr.J.Chem., 1966,19,2321-30; Chemiker-Zeitung, 101,6,1977,305-7; Tetrahedron, 2002,58,887-890; Synthesis, 1983,641-645.
In following reaction scheme 6-8, shown several route of synthesis, these schemes are suitable for the benzene sulfonyl chloride that fluoro propyl group is carried in preparation.
Reaction scheme 6:
4-(1,1-difluoro, third-2-yl) benzene-1-sulfonyl chloride intermediate can be made by commercially available 2-phenylpropionic acid.First step a) in, for example, by (HCl, SO under acid catalysis 2cl 2) for example, with alcohol (methyl alcohol or ethanol) esterification, 2-phenylpropionic acid is changed into alkyl ester.Can use reductive agent for example DIBAL (diisobutylaluminium hydride) this ester is reduced into corresponding 2-phenylpropionaldehyde.By the fluorination reagent with suitable, react aldehyde is changed into 1, the fluoro-2-propyl derivatives of 1-bis-, described fluorination reagent is for example DAST (three fluoridize diethylamino sulphur), morpholine-DAST, deoxo-fluor (three fluoridize two (2-methoxy ethyl) amino sulphur), Ishikawa ' s reagent (N, N-diethyl-(1,1,2,3,3,3-hexafluoro propyl group) amine; Journal of FluorineChemistry, 1989,43,371-377) (step b).By following method, by thus obtained 1, the fluoro-2-phenyl-propane of 1-bis-changes into 4-(the fluoro-2-propyl group of 1,1-bis-) benzene sulfonyl chloride: with the direct chlorosulfonylation of chlorsulfonic acid (Heterocycles, 2001,55,9,1789-1803; J.Org.Chem., 2000,65,1399-1406) (step c), or carry out two step method, first prepare sulfonic acid (steps d), then with for example chlorsulfonic acid, phosphorus pentachloride, convert it into SULPHURYL CHLORIDE (Eur.J.Med.Chem., 2002,36,809-828); Under acidic conditions, use Sodium Nitrite by suitable amine precursor diazotization, and react in acetic acid with sulfurous gas (J.Org.Chem., 1960,25,1824-26); By suitable heteroaryl-mercaptan or heteroaryl-benzyl-chlorine for thioether (Synthesis, 1998,36-38; J.Am.Chem.Soc., 1950,74,4890-92) be direct oxidation into corresponding SULPHURYL CHLORIDE.
Synthetic (R)-2-phenylpropionic acid and (the S)-2-phenylpropionic acid of can also using showing in reaction scheme 6 carries out, to generate respectively corresponding chirality 4-(1,1-difluoro, third-2-yl) benzene-1-SULPHURYL CHLORIDE.
Reaction scheme 7:
4-(1,1,1-trifluoropropyl-2-yl) benzene-1-sulfonyl chloride intermediate can be by the route of synthesis that shows in reaction scheme 7 by commercially available 2,2, and the fluoro-1-Phenyl ethyl ketone of 2-tri-makes.Then can by the following method this ketone be changed into 3,3, the fluoro-2-phenyl of 3-tri-propylene: with suitable inner salt for example methylene radical-triphenylphosphine (by by halogenation first base triphenyl phosphonium and suitable alkali for example lithium diisopropylamine or potassium tert.-butoxide react make) carry out Wittig reaction, or according to Horner-Emmons reaction, by ketone and suitable phosphonic acid ester for example methyl-phosphorous acid diethyl ester and suitable alkali for example lithium diisopropylamine or potassium tert.-butoxide react.Then can be for example, by catalytic hydrogenation (Pd-C) obtained 3,3, the fluoro-2-phenyl of 3-tri-propylene is reduced into saturated alkane, converts it into SULPHURYL CHLORIDE afterwards by the method for describing in reaction scheme 6.
The synthetic of reaction scheme 7 can also carry out with the chiral catalyst for olefin hydrogenation, to prepare corresponding chirality 4-(1,1,1-trifluoropropyl-2-yl) benzene-1-SULPHURYL CHLORIDE.
Reaction scheme 8:
4-(1,1,1-trifluoropropyl-2-yl) benzene-1-SULPHURYL CHLORIDE can also be made by commercially available 1-phenyl-ethyl ketone by four step method as shown in reaction scheme 8.Can this ketone be changed into trifluoromethyl hydroxy intermediate (Journal of Organic Chemistry, 2000,65,8848-8856 by reacting with trimethylammonium-trifluoromethyl-silicomethane; Journal of Fluorine Chemistry, 2003,122,243-246), then can convert it into trifluoromethyl bromine (Journal of the American Chemical Society, 1987,109,2435-4).For example, by catalytic hydrogenation (Pd-C), carry out dehydrogenation, then by aforesaid method, change into SULPHURYL CHLORIDE.
The example of spendable solvent has ether, for example ether, diisopropyl ether, methyl tertiary butyl ether or tetrahydrofuran (THF), aprotic polar solvent is dimethyl formamide, methyl-sulphoxide, glycol dimethyl ether and acetonitrile for example, aromatic hydrocarbon is toluene and dimethylbenzene for example, ketone is acetone or methyl ethyl ketone for example, hydrocarbon is methylene dichloride, trichloromethane and ethylene dichloride for example, ester is ethyl acetate and methyl-butyrate for example, carboxylic acid is acetic acid or propionic acid for example, and alcohol for example methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, 2-butanols and the trimethyl carbinol.
If necessary, can exist in alkali and the proton discharging in reaction.Suitable alkali comprises mineral alkali for example sodium carbonate, salt of wormwood, sodium bicarbonate or saleratus, and alkoxide for example sodium methylate or sodium ethylate, alkalimetal hydride is sodium hydride for example, and organometallic compound for example butyl lithium compounds or alkyl magnesium compound, or alkaloid for example triethylamine or pyridine.A rear compound can play solvent action simultaneously.
Crude product is separated in a usual manner, such as by filtering, by solvent distillation or extract from reaction mixture etc.Purifying gained compound in a usual manner, recrystallization from solvent for example, chromatography, or change into acid salt.
Acid salt is in a usual manner by mixing free alkali with corresponding acid, in the solution of organic solvent, mix and make if appropriate, described organic solvent is for example methyl alcohol, ethanol or propyl alcohol of lower alcohol for example, ether is methyl tertiary butyl ether or Di Iso Propyl Ether for example, ketone is acetone or methyl ethyl ketone for example, or ester ethyl acetate for example.
Because it is to other acceptor D for example 1acceptor, D 4acceptor, α 1-suprarenal gland energy and/or α 2-adrenergic receptor, muscarine energy acceptor, Histamine Receptors, opiate receptor and dopamine D particularly 2the low-affinity of acceptor, so surprisingly highly selective dopamine D of the compounds of this invention of formula I 3receptors ligand, and as D 2the typical psychosis of receptor antagonist is compared, and it produces lighter side effect.The compounds of this invention can be the dopamine D that comprises PAA 3receptor stimulant, or comprise the dopamine D of part antagonistic activity 3receptor antagonist.
The compounds of this invention is for D 3the high affinity of acceptor is to be conventionally less than 50nM (nmol/l), to be preferably less than 10nM and to be particularly less than the low-down extracorporeal receptor binding constant (K of 5nM i(D 3) value) reflection.[ 125i]-iodosulpride displacement can, for example, for measuring for D 3the receptor binding assays of the binding affinity of acceptor.
The selectivity of the compounds of this invention, i.e. the ratio K of receptors bind constant i(D 2)/K i(D 3), be generally at least 50, preferably at least 100, more preferably at least 150.[ 3h] SCH23390, [ 125i] iodosulpride or [ 125i] displacement of spiperone can be for example for carrying out D 1, D 2and D 4the research of acceptor.
Due to its binding characteristic, the compounds of this invention can be used for the treatment of dopamine D 3the disease that receptors ligand reacts (or correspondingly its to using dopamine D 3receptor ligands for treatment is responsive), that is, the compounds of this invention is used for the treatment of effectively wherein to dopamine D 3the impact of acceptor (adjusting) causes clinical condition to improve or cause those Medicine diseases or the disease of disease cured.The example of these diseases is central nervous system disorders or disease.
Central nervous system disorders or disease are interpreted as and mean to affect spinal cord and the illness of brain particularly.Within meaning the present invention, term " illness " represents conventionally to be regarded as pathologic state or function and the obstacle that can show with the form of special sign, symptom and/or dysfunction and/or abnormal.Although the present invention treatment take single illness abnormal or pathological state be target, for being coupled to each other in the cause of disease pattern that is combined as be syndromic some abnormal be also possible, described syndrome can be treated according to the present invention.
The illness that can treat according to the present invention, particularly, P&N obstacle.These obstacles comprise, particularly, organ obstacle, comprises symptom obstacle, and for example acute external source reactive psychosis, or organ or for example external cause relevant to metabolic disturbance, infection and incretopathy are followed psychosis; Endogenous psychosis, for example schizophrenia and schizophrenia type and delusional disorder; Affective disorder, for example dysthymia disorders, mania and/or manic-dysthymia disorders; And the mixed form of above-mentioned obstacle; Neurosis and body type obstacle and with obstacle that stress be relevant; Divergence type obstacle, for example the loss of consciousness, comprises consciousness, double consciousness and personality disorder; Attention disorders and wake/sleeping behavior, for example, in behavior disorder and the emotional handicap of children and adolescence outbreak, for example children ' s activity is excessive, amentia, particularly attention deficit disorder (attention deficit disorder (ADD)), dysmnesia and cognitive disorder, for example learning and memory lowers (cognitive function attenuating), dementia, narcolepsy and somnopathy, for example restless leg syndrome; Development obstacles; Anxiety state, delirium; Sexual life obstacle, for example impotence in the male sex; Eating disorder, for example apositia or bulimia; Habituation; And other unspecified psychiatric disturbance.
The illness that can treat according to the present invention also comprise Parkinson's disease and epilepsy and, particularly, relevant affective disorder therewith.
Addictive disorders comprises mental disorder and the behavior disorder that the abuse by the peychoactive medicine as pharmaceuticals and narcotic and so on causes, and other addictive disorders, and (not in addition) is for example addicted to gambling.The example of addicted substance is: opioid (for example morphine, heroine and morphine monomethyl ether); Cocaine; Nicotine; Alcohol; With the interactional material of GABA chloride channel complex body, tranquilizer, soporific and tranquilizer, for example benzodiazepine is removed from office; LSD; Cannaboid; Ideomotor movement stimulator, for example 3,4-methylene radical dioxy base-N-methamphetamine hydrochloride (magic potion); Amphetamine and amphetamine class material be Methylphenidylacetate and other stimulator that comprises caffeine for example.What take in especially is opioid, Cocaine, amphetamine or amphetamine class material, Nicotine and alcohol.
With regard to treatment addictive disorders, particularly preferably be the compounds of this invention that itself does not there is the formula I of any peychoactive effect.This also can observe in the test of carrying out with rat, and described rat is in administration according to the present invention after operable compound, and the peychoactive material that has reduced them is the automedication of Cocaine for example.
According to another aspect of the present invention, the compounds of this invention is applicable to treat its reason at least partly owing to dopamine D 3the illness of the abnormal activity of acceptor.
According to another aspect of the present invention, in the meaning of favourable pharmacological agent, the present invention treats sensing, particularly, and by by the mating partner of preferred exogenous administration (part) and dopamine D 3receptors bind and affected illness.
Can be enough the disease of the compounds of this invention treatment normally take carry out the passing in time of the above-mentioned illness of sexual development-be and change-as feature; Conventionally, seriousness increases and illness may mutually and be closed, or can occur other illness the illness except having existed.
The compounds of this invention can be used for the treatment of many signs, illness and/or the dysfunction relevant with central nervous system disease, particularly above-mentioned illness.Sign, illness and/or dysfunction comprise, for example, upset with relations of fact, lack the ability that understands custom social regulation or existence demand or meet custom social regulation or existence demand, disposition changes, individual's driven nature is for example hungry, sleep, the change of serious hope etc., personality change, emotional instability particularly, mirage, oneself's disturbance, upset, ambivalence, autism, depersonalization and false sense, illusion, speech changes, lack synkinesis, the paces of short stride, the curved position of body and four limbs, tremble, lack facial expression, language is dull, dysthymia disorders, indifferently, spontaneous and decisive being obstructed, lack sociability, anxiety disorder, nervous excitation, stutter, social phobia, panic, the Withrawal symptom relevant with dependency, fanatic symptom, excitement and perplexity, have the fidgets, dyskinetic syndrome and spasm illness, for example Huntington chorea and Gilles-de-la-Tourette ' s syndrome, vertiginous syndrome is peripheral position for example, rotate and swing dizzy, melancholia, hysteria, hypochondria etc.
In implication of the present invention, the present invention's treatment also comprises prophylactic treatment (prevention), particularly recurrence prevention or stage prevention, and treat acute or chronic sign, illness and/or dysfunction.Described treatment can be to take symptom as object, and for example symptom suppresses.It can be that short-term is effective, take mid-term as directed, or can be long-term treatment, for example, in the situation that maintaining treatment.
Therefore, the compounds of this invention is preferably applicable to treat central nervous system disease, especially for treatment affective disorder, and neurosis disorder, stress disorder, body shape obstacle and psychosis, in particular for treatment schizophrenia and dysthymia disorders.Because it is to dopamine D 3the high-affinity of acceptor, the compounds of this invention is also applicable to treat renal tubal dysfunction, particularly by diabetes, causes (referring to WO00/67847) and renal tubal dysfunction that especially diabetic nephropathy causes.
In the scope for the treatment of, the application of described the compounds of this invention relates to method.In the method, the individuality being treated, preferred mammal, the particularly mankind, productivity animal or domestic animal are prepared-delivered medicine to one or more compounds of significant quantity-conventionally according to pharmacy and veterinary science practice.No matter whether such treatment indicates, which kind of and with form carry out, depend on individual situation and by via medical evaluation (diagnosis), described medical evaluation is considered existing sign, illness and/or dysfunction, develops into the risk of special sign, illness and/or dysfunction.
Conventionally, the present invention's treatment realizes by single or repetition administration every day, common suitable in the situation that, or alternately, with other active compound or the preparation administration that contains active compound, like this by per daily dose, in the situation that the preferred about 0.1-1000mg/kg body weight of oral administration, or about 0.1-100mg/kg body weight, delivers medicine to the individuality being treated in the situation that parenteral is given.
The invention still further relates to for the preparation for the treatment of individuality-preferred mammal, the particularly mankind, productivity animal or domestic animal-pharmaceutical composition.Therefore, the form administration with pharmaceutical composition by part conventionally, described pharmaceutical composition comprises pharmaceutically acceptable vehicle, and at least one the compounds of this invention and, suitable in the situation that, other active compound.These compositions can, for example, oral, rectum, through skin, intravenously, intramuscular or intranasal administration.
Suitable pharmaceutical preparation is solid Types of Medicine, powder agent for example, granule, tablet, particularly film-coated tablets, lozenge, pouch agent, cachet, sweet tablet tablet, capsule, for example hard gel wafer and soft gel wafer, suppository or sheath Types of Medicine, semi-solid Types of Medicine, ointment for example, emulsifiable paste, hydrogel, paste or plaster, and liquid Types of Medicine, solution for example, emulsion, the particularly emulsion of oil in water, suspension liquor, lotion for example, injection and infusion agent, eye drops and auristillae.Implanting releasing device can be for administration inhibitor of the present invention.In addition, also can use liposome or droplet.
When preparing composition, can be optionally by one or more mixed with excipients or dilution for the compounds of this invention.Vehicle can be as the carrier of active compound or the solid of medium, semisolid or fluent material.
Suitable vehicle is listed in expert's Medical monographs.In addition, preparation can comprise pharmaceutically acceptable carrier or conventional auxiliary substance, for example glidant; Wetting agent; Emulsifying agent and suspension agent; Sanitas; Antioxidant; Counter irritant; Sequestrant; Dressing auxiliary; Emulsion stabilizer; Film forming agent; Gel former; Smell screening agent; Taste corrigent; Resin; Hydro-colloid; Solvent; Solubilizing agent; Neutralizing agent; Diffusion accelerator; Pigment; Quaternary ammonium compound; Stuffing and excessively fatting agent again; Raw material or oil for ointment, emulsifiable paste; Silicone derivative; Scatter auxiliary; Stablizer; Sterilant; Suppository bases; Tablet auxiliary, for example tackiness agent, filler, glidant, disintegrating agent or dressing; Propelling agent; Siccative; Opalizer; Thickening material; Wax; Softening agent and slab oil.About the preparation of this respect, take expertise as basis, Fiedler for example, H.P., Lexikon der Hilfsstoffe f ü rPharmazie, Kosmetik und angrenzende Gebiete[Encyclopedia of auxiliarysubstances for pharmacy, Cosmetics and related fields], 4 thedition, Aulendorf:ECV-Editio-Kantor-Verlag, described in 1996.
The following example is to explain the present invention rather than restriction the present invention.
Compound is by d 6proton-NMR in-methyl-sulphoxide or d-chloroform on 400MHz or 500MHz NMR device (Bruker AVANCE) or characterize by mass spectrum, mass spectrum is generally with quick gradient, at C18-material (electronic spraying-ionization (ESI) mode), to go up record by HPLC-MS, or characterizes by fusing point.
(NMR refers to chemical shift (δ) to NMR (Nuclear Magnetic Resonance) spectrum character, counts very much (ppm) represent with hundred. 1in H NMR spectrum, the relative area of displacement is corresponding to the number of particular functional type hydrogen atom in molecule.As for the displacement property of multiplicity, be expressed as unimodal (s), wide unimodal (s.br.), bimodal (d), wide bimodal (d br.), triplet (t), wide triplet (t br.), quartet (q), quintet (quint.) and multiplet (m).
preparation Example:
I. prepare intermediate
A. prepare SULPHURYL CHLORIDE
A.1 4-(the fluoro-1-methyl-ethyl of (S)-2-)-benzene sulfonyl chloride
A.1.1 toluene-4-sulfonic acid (S)-2-phenyl-propyl diester
In solution to 20g (S)-(-)-2-phenyl-1-propanol in 240ml methylene dichloride, add 28g Tosyl chloride (146.8mmol) in batches.In stirring at room, after 18 hours, by organic phase 100ml water washing, by dried over mgso, filter, and the solvent was evaporated under reduced pressure, obtain this title compound of 43g.
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.65(d，2H)，7.15-7.3(m，5H)，7.1(d，2H)，4.0-4.1(m，2H)，3.1(m，1H)，2.4(s，3H)，1.3(d，3H)。
A.1.2 (the fluoro-1-methyl-ethyl of (S)-2-)-benzene
9.62g toluene-4-sulfonic acid (S)-2-phenyl-propyl diester (33.13mmol) is dissolved in 80ml poly(oxyethylene glycol) 400, add 9.62g Potassium monofluoride (165.6mmol), reaction mixture is stirred 3 days in 50 ℃, and stir again 2 days in 55-70 ℃.To react by 150ml saturated aqueous sodium chloride and process, use extracted with diethyl ether three times, and by the organic layer dried over mgso merging, filter, and solvent removed under reduced pressure.Crude product is carried out to purifying by silica gel chromatography, use cyclohexane/ethyl acetate 15% as eluent.Isolate the required product of 2.85g, contain～25% elimination byproduct of reaction.
1h-NMR (CDCl 3, 400MHz): δ [ppm] 7.2-7.4 (m, 5H), 4.3-4.6 (several m, 2H), 3.15 (m, 1H).1.3(m，3H)。
A.1.3 4-(the fluoro-1-methyl-ethyl of (S)-2-)-benzene sulfonyl chloride
3.5g (the fluoro-1-methyl-ethyl of (S)-2-)-benzene (25.32mmol) is dissolved in 80ml methylene dichloride.In 0-5 ℃ of dropping, be dissolved in the 11.81g chlorsulfonic acid (101.31mmol) in 20ml methylene dichloride.Reaction mixture, in stirring at room 30 minutes, and is stirred 2 hours in 30 ℃.Solvent is evaporated.150ml ether is added in this resistates, with 150ml water washing once, and by organic layer dried over mgso, filter, and the solvent was evaporated under reduced pressure.Resistates is carried out to purifying by silica gel chromatography, with normal heptane-methylene dichloride (6:4), as eluent, obtain this title compound of 1.5g.
1H-NMR(CDCl 3，400MHz)：δ[ppm]8.0(d，2H)，7.5(d，2H)，4.5(dd，2H)，3.25(m，1H)，1.4(d，3H)。
A.2 4-(the fluoro-1-methyl-ethyl of (R)-2-)-benzene sulfonyl chloride
A.2.1 toluene-4-sulfonic acid (R)-2-phenyl-propyl diester
According to the similar approach with for the synthesis of toluene-4-sulfonic acid (S)-2-phenyl-propyl diester, but use (R)-2-phenyl-1-propanol, be prepared into this title compound.
A.2.2 (the fluoro-1-methyl-ethyl of (R)-2-)-benzene
This title compound is prepared as above-mentioned synthetic (the fluoro-1-methyl-ethyl of (S)-2-)-benzene, but replaces toluene-4-sulfonic acid (S)-2-phenyl-propyl diester with toluene-4-sulfonic acid (R)-2-phenyl-propyl diester.
1h-NMR (CDCl 3, 400MHz): δ [ppm] 7.2-7.4 (m, 5H), 4.3-4.6 (several m, 2H), 3.15 (m, 1H).1.3(m，3H)。
A.2.3 4-(the fluoro-1-methyl-ethyl of (R)-2-)-benzene sulfonyl chloride
1.3g (the fluoro-1-methyl-ethyl of (R)-2-)-benzene (9.4mmol) is dissolved in 50ml methylene dichloride.In 0-5 ℃ of dropping, be dissolved in the 1.1g chlorsulfonic acid (9.4mmol) in 10ml methylene dichloride.Reaction mixture is stirred 20 minutes at 0-5 ℃, then add the solution in 2.15g phosphorus pentachloride 40ml methylene dichloride.This compound of reaction is stirred 30 minutes at 0-5 ℃, and stirring at room 1 hour.Solvent is evaporated, add 100ml ether, by this mixture with 150ml water washing once, and by organic layer dried over mgso, filter, and solvent removed under reduced pressure.Crude product is carried out to purifying by silica gel chromatography, with normal heptane-methylene dichloride (1:1), as eluent, obtain this title compound of 0.261g.
1H-NMR(CDCl 3，400MHz)：δ[ppm]8.0(d，2H)，7.5(d，2H)，4.5(dd，2H)，3.25(m，1H)，1.4(d，3H)。
A.3 4-(the fluoro-1-methyl-ethyl of 2-)-benzene sulfonyl chloride
According to the similar approach with for the preparation of 4-(the fluoro-1-methyl-ethyl of (S)-2-)-benzene sulfonyl chloride, but step a.3.1 in from 2-phenyl-1-propanol, be prepared into this title compound.
1H-NMR(CDCl 3，400MHz)：δ[ppm]8.0(d，2H)，7.5(d，2H)，4.5(dd，2H)，3.25(m，1H)，1.4(d，3H)。
A.4 4-(the fluoro-1-methyl fluoride-ethyl of 2-)-benzene sulfonyl chloride
A.4.1 (the fluoro-1-methyl fluoride-ethyl of 2-)-benzene
4g3-phenyl pentanedioic acid (19.21mmol) is suspended in 350ml methylene dichloride.In room temperature, add 6.5g xenon difluoride (38.42mmol), and by reaction mixture in stirring at room 18 hours.By organic phase with the washing of 975ml6% sodium bicarbonate aqueous solution once, by dried over mgso, filter, and solvent is evaporated.Remaining resistates is distilled in the bath temperature of 123 ℃ at 21mm, obtain this title compound of contain～50%4-of 0.78g (the fluoro-1-methyl-ethyl of 2-)-benzene.
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.2-7.4(m，5H)，4.6-4.8(dd，4H)，3.3(m，1H)。
A.4.2 4-(the fluoro-1-methyl fluoride-ethyl of 2-)-benzene sulfonyl chloride
According to the similar approach with for the preparation of 4-(the fluoro-1-methyl-ethyl of (S)-2-)-benzene sulfonyl chloride, but use 5 equivalent chlorsulfonic acids, obtain this title compound of 0,12g.
1H-NMR(CDCl 3，400MHz)：δ[ppm]8.05(d，2H)，7.55(d，2H)，4.75(dd，4H)，3.4(m，1H)。
A.5 4-(3,3,3-trifluoro propyl)-benzene sulfonyl chloride
According to the above-mentioned method that is used for synthesizing 4-(the fluoro-1-methyl-ethyl of (S)-2-)-benzene sulfonyl chloride, by (3,3,3-trifluoro propyl)-benzene of commercially available acquisition, obtain this title compound of 2.9g.
1H-NMR(CDCl 3，400MHz)：δ[ppm]8.0(d，2H)，7.45(d，2H)，3.0(t，2H)，2.45(m，2H)。
A.6 4-(2,2,2-trifluoroethyl)-benzene sulfonyl chloride
According to J.Org.Chem., the method for describing in 1960,25,1824-26, (2,2,2-the trifluoroethyl)-benzene by commercially available acquisition, obtains this title compound.
1H-NMR(CDCl 3，400MHz)：δ[ppm]8.05(d，2H)，7.55(d，2H)，3.5(q，2H)。
A.7 4-(3-fluoropropyl)-benzene sulfonyl chloride
A.7.1 (3-fluoropropyl)-benzene
15.6g tri-is fluoridized to diethylamino sulphur (DAST, 96.91mmol) to be dissolved in 18ml methylene dichloride.In 0-5 ℃ of dropping, be dissolved in the 12g3-phenyl-1-propanol (88.1mmol) in 30ml methylene dichloride.Reaction mixture is stirred to 18h hour, add after 30ml methylene dichloride, be poured on 100ml frozen water.Organic layer is separated, by dried over mgso, filter, and solvent is evaporated.Crude product is carried out to purifying by bathing temperature distillation at 20mm in 106 ℃, obtain this title compound of 7.4g.
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.1-7.3(m，5H)，4.4(dt，2H)，2.7(m，2H)。2.0(m，2H)。
A.7.2 4-(3-fluoropropyl)-benzene sulfonyl chloride
4.1g (the fluoro-propyl group of 3-)-benzene (29.67mmol) is dissolved in 40ml methylene dichloride.In 0-5 ℃ of dropping, be dissolved in the 6.91g chlorsulfonic acid (59.34mmol) in 10ml methylene dichloride.Reaction mixture is stirred 45 minutes at 0-5 ℃, then add 6.8g phosphorus pentachloride (32.63mmol) to be dissolved in the solution in 50ml methylene dichloride.Reaction mixture is stirred 1 hour at 5-10 ℃.By solvent evaporation, add 150ml ether, with the washing of 150ml frozen water, by organic layer dried over mgso, filter, and the solvent was evaporated under reduced pressure.Crude product is carried out to purifying by silica gel chromatography, with normal heptane-methylene dichloride (11:9), as eluent, obtain this title compound of 5.5g.
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.95(d，2H)，7.45(d，2H)，4.5(dt，2H)，2.9(t，2H)，2.05(m，2H)。
A.8 4-(the fluoro-cyclopropyl of 2,2-bis-)-benzene sulfonyl chloride
Except only using 1.1 equivalent phosphorus pentachlorides, all the other by (2,2-difluoro cyclopropyl)-benzene of commercially available acquisition, obtain this title compound of 2.07g all according to the method for the synthesis of (3-fluoropropyl)-benzene sulfonyl chloride.
1H-NMR(CDCl 3，400MHz)：δ[ppm]8.0(d，2H)，7.45(d，2H)，2.85(m，1H)，2.0(m，1H)，1.75(m，1H)。
A.9 the bromo-4-trifluoromethoxy-benzene sulfonyl chloride of 3-
The bromo-2-of 2.0g1-(three fluoro-methoxyl groups) benzene (8.3mmol) is dissolved in 30ml methylene dichloride.In 0-5 ℃ of dropping, be dissolved in the 1.06g chlorsulfonic acid (9.13mmol) in 3ml methylene dichloride.By reaction mixture stirring at room 30 minutes.Add again the solution of 5.5 equivalent chlorsulfonic acids in methylene dichloride so that reacted.Then carry out standard aftertreatment, and with normal heptane-methylene dichloride (6:4), as eluent, carry out silica gel chromatography and purify, obtain this title compound of 2.19g.
1H-NMR(CDCl 3，400MHz)：δ[ppm]8.3(d，1H)，8.05(dd，1H)，7.5(dd，1H)。
A.10 4-(2-fluoro ethyl)-benzene sulfonyl chloride
A.10.1 (2-fluoro ethyl)-benzene
According to the method for the synthesis of (3-fluoropropyl)-benzene, by the 2-phenyl-ethanol of commercially available acquisition, obtain this title compound of 6.8g.
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.1-7.3(m，5H)，4.6(m，1H)，4.45(m，1H)，2.95(m，1H)，2.9(m，1H)。
A.10.2 4-(2-fluoro ethyl)-benzene sulfonyl chloride
According to the method for the synthesis of 4-(the fluoro-1-methyl-ethyl of (R)-2-)-benzene sulfonyl chloride, obtain this title compound of 3.55g.
1H-NMR(CDCl 3，400MHz)：δ[ppm]8.0(d，2H)，7.5(d，2H)，4.7(dt，2H)，3.05-3.2(dt，2H)。
A.11 5-propyl group thiophene-2-SULPHURYL CHLORIDE
According to the similar approach with for the preparation of (the fluoro-propyl group of 3-)-benzene sulfonyl chloride, but only use 1 equivalent phosphorus pentachloride, be prepared into this title compound.
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.7(d，1H)，6.85(d，1H)，2.9(t，2H)，1.75(m，2H)，1.0(t，3H)。
A.12 4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-benzene sulfonyl chloride
A.12.1 1-methyl 4-phenyl-1H-pyrazoles
1g2-phenyl mda (6.75mmol) is dissolved in 25ml ethanol.Add 0.36mlN-methyl-hydrazine (6.75mmol), reaction mixture is stirred 4 hours under refluxing, solvent removed under reduced pressure, obtain this title product of 1.09g.
ESI-MS：159.1IM+H]+
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.75(s，1H)，7.6(s，1H)，7.45(d，2H)，7.35(t，2H)，7.2(t，1H)，3.9(s，3H)
A.12.2 4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-benzene sulfonyl chloride
0.5g1-methyl 4-phenyl-1H-pyrazoles (3.16mmol) is dissolved in 20ml methylene dichloride.Add 0.232ml chlorsulfonic acid in 0 ℃, and by reaction mixture ice-cold lower stirring 1 hour.Add again 0.7ml chlorsulfonic acid, and mixture is stirred 30 minutes at 0 ℃, then at 50 ℃, stir 90 minutes.These two are separated, and Bing Ba lower floor is poured on ice, by extracted with diethyl ether twice, by dried over mgso, filter, and the solvent was evaporated under reduced pressure, obtains this title product of 0.496g.
1H-NMR(CDCl 3，400MHz)：δ[ppm]8.0(d，2H)，7.85(s，1H)，7.75(s，1H)，7.65(d，2H)，4.0(s，3H)。
A.13 4-(1,1,1-trifluoropropyl-2-yl) benzene sulfonyl chloride and
2-(1,1,1-trifluoropropyl-2-yl) benzene sulfonyl chloride
Scale preparation according to the method for general introduction in scheme 7 with 14g.2-(1,1,1-trifluoropropyl-2-yl) benzene sulfonyl chloride is the by product of this reaction.
4-(1,1,1-trifluoropropyl-2-yl) benzene sulfonyl chloride:
MS(ESI)m/z：273.1[M+H] +
1H-NMR(DMSO-d 6)：δ[ppm]7.62(d，2H)，7.33(d，2H)，3.81(m，1H)，1.42(d，3H)。
2-(1,1,1-trifluoropropyl-2-yl) benzene sulfonyl chloride:
MS(ESI)m/z：273.1[M+H] +
A.14 4-(1,1-difluoro, third-2-yl) benzene sulfonyl chloride and
2-(1,1-difluoro, third-2-yl) benzene-1-SULPHURYL CHLORIDE
Scale preparation according to the method for general introduction in scheme 6 with 11g.2-(1,1-difluoro, third-2-yl) benzene-1-SULPHURYL CHLORIDE is the by product of this reaction.
4-(1,1-difluoro, third-2-yl) benzene sulfonyl chloride:
MS(ESI)m/z：255.0[M+H] +
1H-NMR(DMSO-d 6)：δ[ppm]8.03(d，2H)，7.55(d，2H)，5.88(dt，1H)，3.34(m，1H)，1.47(d，3H)。
13C-NMR(DMSO-d 6)：δ[ppm]146.43，143.54，129.77，127.28，117.06(t)，43.76，13.78.
2-(1,1-difluoro, third-2-yl) benzene-1-SULPHURYL CHLORIDE:
Scale with 110mg is separated by chromatography
MS(ESI)m/z：255.0[M+H] +
1H-NMR(DMSO-d 6)：δ[ppm]8.15(d，1H)，7.77(t，1H)，7.70(d，1H)，7.54(t，1H)，5.99(dt，1H)，4.43(m，1H)，1.51(d，3H)。
13C-NMR(DMSO-d 6)：δ[ppm]143.45，138.63，135.53，130.93，129.04，128.17，116.61(t)，38.38，13.68.
B. prepare the fluoro-propyl diester of toluene-4-sulfonic acid 3-
The fluoro-propyl alcohol of 5g3-(64.03mmol) and 18ml triethylamine (129.32mmol) are dissolved in 50ml methylene dichloride.At 0-5 ℃, add 12.9g toluene-4-sulfonyl chloride (67.66mmol), and this reaction mixture is modified in stirring at room 18.Carry out standard aftertreatment, obtained the fluoro-propyl diester of 13.7g toluene-4-sulfonic acid 3-.
ESI-MS：233.1[M+H] +
II. prepare Compound I
Embodiment 1
4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
1.1 (S)-2-phenyl-Succinic acid dimethylesters
5g (S)-2-phenylsuccinic acid (25.75mmol) is dissolved in 50ml methyl alcohol.At 4 ℃, drip 4.7ml thionyl chloride (64.37mmol).By this reaction mixture, stirring at room 2 hours, the solvent was evaporated under reduced pressure.Residue resistates is dissolved in to ether, uses saturated NaHCO 3solution washing 1 time, extracts with ether again, and by the organic layer dried over mgso merging, filtration, and be evaporated to dryly, obtained the required product of 5.8g.
ESI-MS：223.1[M+H] +
1.2 (S)-2-phenyl-butane-Isosorbide-5-Nitrae-glycol
Ice-cooled, lower 2.54g lithium aluminium hydride (66.95mmol) is suspended in 25ml tetrahydrofuran (THF).At 5-10 ℃, add lentamente 5.8g (the S)-2-phenylsuccinic acid dimethyl ester (25.75mmol) being dissolved in 25ml tetrahydrofuran (THF).Continue to stir 15 minutes, then drip 15ml tetrahydrofuran (THF)/water (1:1).With concentrated hydrochloric acid, this suspension is adjusted to pH3-4, filters and use washed with dichloromethane filter.Filtrate is evaporated to dry, is placed in ether, with saturated sodium bicarbonate solution washing, with ether, extract again, and by the organic layer dried over mgso merging, filtration, and the solvent was evaporated under reduced pressure, obtained 4.2g glycol.
ESI-MS：189.1[M+Na] +
1H-NMR(CDCl 3)：δ[ppm]7.25-7.4(m，2H)，7.15-7.3(m，3H)，4.2-4.35(m，2H)，3.2(m，1H)，3.1(m，1H)，2.1-2.3(m，3H)。
1.3 methylsulfonic acids (S)-4-methylsulfonyl oxygen base-3-phenyl-butyl ester
4.19g (S)-2-phenyl-butane-Isosorbide-5-Nitrae-glycol (25.21mmol) is dissolved in 50ml methylene dichloride.Add 10.53ml triethylamine (75.6mmol), and add 5ml methylsulfonyl chloride (64.34mmol) under ice-cooled.Continue to stir 15 minutes, then add 40ml water.Isolate organic layer, by water dichloromethane extraction.By the organic layer dried over mgso merging, filter, and the solvent was evaporated under reduced pressure, obtained 8.37g product.
1.4 (S)-3-phenyl-1-propyl group-tetramethyleneimine
2.0g methylsulfonic acid (S)-4-methylsulfonyl oxygen base-3-phenyl-butyl ester (5.51mmol) is dissolved in 5ml n-propyl amine (60.82mmol).This reaction, stirring at room 15 hours, is added to ether, organic phase is washed with water twice.Water is extracted once with ether again, merge organic layer, by dried over mgso, filter, and the solvent was evaporated under reduced pressure, obtained 1.09g product.
ESI-MS：190.1[M+H] +
1.5 (S)-3-(4-nitro-phenyl)-1-propyl group-tetramethyleneimine
Argon gas and ice-cooled under, 0.3g (S)-3-phenyl-1-propyl group-tetramethyleneimine (1.48mmol) is dissolved in the 2ml vitriol oil.With on a small quantity repeatedly mode add 165.16mg saltpetre (1.63mmol).This reaction, ice-cooled lower stirring 15 minutes, stirring at room 15 hours, and is poured on trash ice.The aqueous solution is alkalized with 25% sodium hydroxide, use extracted with diethyl ether 3 times, water is extracted once with ether again, merge organic layer, by dried over mgso, filter, and the solvent was evaporated under reduced pressure, obtained 0.326g brown oil.Second reaction obtained the required product of other 0.919g.
ESI-MS：235.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]8.15(d，2H)，7.45(d，2H)，3.4-3.5(m，1H)，2.9-3.0(m，1H)，2.75(m，1H)，2.3-2.6(m，4H)，1.8-1.9(m，1H)，1.5-1.65(m，3H)，0.95(m，3H)。
1.6 (S)-3-(4-amino-phenyl)-1-propyl group-tetramethyleneimine
0.907g (S)-3-(4-nitro-phenyl)-1-propyl group-tetramethyleneimine (3.59mmol) is dissolved in 20ml methyl alcohol, adds 7.0g tindichloride (31.02mmol), and this reaction mixture refluxed is stirred 1 hour.Methyl alcohol is evaporated, add 60ml1N sodium hydroxide and methylene dichloride, separation of phases after fully stirring.By dichloromethane extraction twice for water, merge organic layer, by dried over mgso, filter, and the solvent was evaporated under reduced pressure, obtained the crude product of 0.744g aminocompound.
ESI-MS：205.2[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 6.9 (d, 2H), 6.45 (d, 2H), 4.7 (s, wide, 2H), 3.1 (m, 1H), 2.85 (m, 1H), 2.65 (m, 1H), 2.55 (m, 1H), 2.25-2.45 (m, 3H), 2.1 (m, 1H), 1.65 (m, 1H), 1.4-1.5 (m, 2H), 0.85 (m, 3H).
1.7 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
0.4g (S)-3-(4-amino-phenyl)-1-propyl group-tetramethyleneimine (1.96mmol) and 0.407mg of4-sec.-propyl-phenyl SULPHURYL CHLORIDE (1.86mmol) are dissolved in 15ml tetrahydrofuran (THF).Add 0.82ml triethylamine (5.87mmol), this reaction mixture is stirred 15 hours.The solvent was evaporated under reduced pressure, resistates water treatment, with sodium hydroxide, is adjusted to alkaline pH.Water layer extracted with diethyl ether 3 times, merge organic layer, by dried over mgso, filter, and the solvent was evaporated under reduced pressure.Crude product, by silica gel chromatography purifying, as eluent, has been obtained to 0.225g purified product by ethyl acetate/methanol (2.5-3%).Product is dissolved in 15ml ether and 1ml methylene dichloride, adds the solution of 0.61ml1N HCl in ether, then after having formed precipitation, reduction vaporization, obtained 0.235g white precipitate.
ESI-MS：387.2[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 11.3 and 11.1 (2s, wide, 1H), 10.35 (m, 1H), 7.7 (d, 2H), 7.4 (d, 2H), 7.15-7.3 (m, 2H), 7.1 (m, 2H), 3.2-3.8 (several m, 4H), 2.85-3.15 (several m, 4H), 2.3 (m, 1H), 1.8-2.0 (m, 1H), 1.6-1.75 (m, 2H), 1.15 (d, 6H), 0.9 (m, 3H).
Embodiment 2
4-(1,1-dimethyl-propyl group)-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use commercially available 4-(1,1-dimethyl-propyl group) benzene sulfonyl chloride, has obtained the required product of 0.219g.
ESI-MS：415.5[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 11.3 and 11.1 (2s, wide, 1H), 10.3 (m, 1H), 7.7 (d, 2H), 7.5 (d, 2H), 7.1-7.3 (m, 2H), 7.1 (m, 2H), 3.15-3.8 (several m, 4H), 2.85-3.15 (several m, 3H), 2.3 (m, 1H), 1.8-2.0 (m, 1H), 1.5-1.75 (several m, 4H), 1.2 (s, 6H), 0.9 (m, 3H), 0.55 (m, 3H).
Embodiment 3
4-(sec.-propyl)-N-[4-((S)-1-allyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
3.1 (S)-1-allyl group-3-phenyl-tetramethyleneimine
According to the synthetic method with identical described in preparation (S)-3-phenyl-1-propyl group-tetramethyleneimine, use allyl amine to obtain the required product of 1.3g.
ESI-MS：188.2[M+H] +
3.2 (S)-1-allyl group-3-(4-nitro-phenyl)-tetramethyleneimine
Synthetic method according to identical described in preparation (S)-3-(4-nitro-phenyl)-1-propyl group-tetramethyleneimine, has obtained the required product of 1.27g.
ESI-MS：233.3[M+H] +
1H-NMR(CDCl 3)：δ[ppm]8.15(d，2H)，7.4(d，2H)，5.85-6.0(m，1H)，5.2(m，1H)，5.1(m，1H)，3.4-3.5(m，1H)，3.05-3.2(m，2H)，3.0(m，1H)，2.75(m，2H)，2.6(m，1H)，2.3-2.4(m，1H)，1.8-1.9(m，1H)。
3.3 (S)-1-allyl group-3-(4-amino-phenyl)-tetramethyleneimine
Synthetic method according to identical described in preparation (S)-3-(4-nitro-phenyl)-1-propyl group-tetramethyleneimine, has obtained the required product of 1.01g.
ESI-MS：203.1[M+H] +
3.4 4-(sec.-propyl)-N-[4-((S)-1-allyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, obtained the required product of 0.184g.
ESI-MS：385.1[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 11.8 and 11.5 (2s, wide, 1H), 10.45 (m, 1H), 7.7 (d, 2H), 7.4 (d, 2H), 7.2-7.3 (m, 2H), 7.1 (m, 2H), 6.0 (m, 1H), 5.4-5.55 (m, 2H), 3.8m (2H), 3.3-3.7 (several m, 3H), 3.2 (m, 1H), 2.9-3.1 (several m, 2H), 2.3 (m, 1H), 1.85-2.05 (m, 1H), 1.15 (s, 6H).
Embodiment 4
4-(sec.-propyl)-N-[4-((R)-1-allyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
4.1 (R)-1-allyl group-3-(4-nitro-phenyl)-tetramethyleneimine
Synthetic method according to identical described in preparation (S)-3-(4-nitro-phenyl)-1-propyl group-tetramethyleneimine, has obtained the required product of 2.1g.
ESI-MS：233.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]8.15(d，2H)，7.4(d，2H)，5.85-6.0(m，1H)，5.2(m，1H)，5.1(m，1H)，3.4-3.5(m，1H)，3.05-3.2(m，2H)，3.0(m，1H)，2.75(m，2H)，2.6(m，1H)，2.3-2.4(m，1H)，1.8-1.9(m，1H)。
4.2 (R)-1-allyl group-3-(4-amino-phenyl)-tetramethyleneimine
Synthetic method according to identical described in preparation (S)-1-allyl group-3-(4-amino-phenyl)-1-propyl group-tetramethyleneimine, has obtained the required product of 1.12g.
ESI-MS：203.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]
4.3 4-(sec.-propyl)-N-[4-((R)-1-allyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, obtained the required product of 0.138g.
ESI-MS：385.1[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 11.65 and 11.45 (2s, wide, 1H), 10.35 (m, 1H), 7.7 (d, 2H), 7.4 (d, 2H), 7.2-7.3 (m, 2H), 7.1 (m, 2H), 6.0 (m, 1H), 5.4-5.55 (m, 2H), 3.8m (2H), 3.3-3.7 (several m, 3H), 3.2 (m, 1H), 2.9-3.1 (several m, 2H), 2.3 (m, 1H), 1.85-2.05 (m, 1H), 1.15 (s, 6H).
Embodiment 5
4-(sec.-propyl)-N-[4-((R)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
By 0.525g4-(sec.-propyl)-N-[4-((R)-1-allyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide (1.37mmol) is dissolved in 15ml ethanol, add 0.075g Pd/C (10%), be warmed to 80 ℃, add the 0.861g ammonium formiate (13.65mmol) being dissolved in 7.5ml water.In stirring at room, after 15 hours, filter out catalyzer, water and washed with dichloromethane.With 1N aqueous sodium hydroxide solution, water is adjusted to pH9, uses dichloromethane extraction 2 times, and the organic layer of merging is washed with saturated nacl aqueous solution, by dried over mgso, filter, and solvent is evaporated to dry, obtained 0.55g n-propyl-and N-remove the mixture of alkyl product.This mixture is dissolved in 25ml methylene dichloride, adds 0.116ml propionic aldehyde (1.6mmol), 0.14ml acetic acid (2.39mmol) and 0.508g sodium triacetoxy borohydride (2.39mmol).In stirring at room after 1 hour, this mixture is evaporated to dry, add water, and with 1N aqueous sodium hydroxide solution pH regulator to pH9.By water layer extracted with diethyl ether 3 times, merge organic layer, by dried over mgso, filter, and be evaporated to dry.By crude product via silica gel chromatography purifying, with ethyl acetate/methanol (17.5%) wash-out, the level that contains product part is merged, reduction vaporization, resistates is distributed between alkalescence (pH9-10) aqueous solution and ether, then with ether, extract for the second time, and wash by ethyl acetate.By the organic layer dried over mgso merging, filtration, and be evaporated to dryly, obtained 0.21g purified product.Resistates is dissolved in 10ml ether, adds the solution of 0.285ml2N HCl in ether.Formed suspension reduction vaporization, to dry, has been obtained to the product of 0.201g as hydrochloride.
ESI-MS：387.2[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 11.4 and 11.3 (2s, wide, 1H), 10.35 (m, 1H), 7.7 (d, 2H), 7.4 (d, 2H), 7.15-7.3 (m, 2H), 7.1 (m, 2H), 3.2-3.8 (several m, 4H), 2.85-3.15 (several m, 4H), 2.3 (m, 1H), 1.8-2.0 (m, 1H), 1.6-1.75 (m, 2H), 1.15 (d, 6H), 0.9 (m, 3H).
Embodiment 6
4-ethyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use commercially available 4-ethyl-benzene sulfonyl chloride, obtained the required product of 0.096g.
ESI-MS：373.3[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 11.35 and 11.15 (2s, wide, 1H), 10.3 (m, 1H), 7.7 (d, 2H), 7.4 (d, 2H), 7.15-7.3 (m, 2H), 7.05 (m, 2H), 2.9-3.8 (several m, 7H), 2.6-2.7 (m, 2H), 2.3 (m, 1H), 1.8-2.0 (m, 1H), 1.6-1.75 (m, 2H), 1.2 (m, 3H), 0.9 (m, 3H).
Embodiment 7
4-trifluoromethoxy-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use commercially available 4-trifluoromethoxy-benzene sulfonyl chloride, obtained the required product of 0.067g.
ESI-MS：429.1[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 11.25 and 11.05 (2s, wide, 1H), 10.65 (m, 1H), 8.0 (m, wide, 4H), 7.2-7.35 (m, 2H), 7.1 (m, 2H), 2.9-3.8 (several m, 7H), 2.3 (m, 1H), 1.8-2.05 (m, 1H), 1.6-1.75 (m, 2H), 0.9 (m, 3H).
Embodiment 8
4-trifluoromethyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use commercially available 4-trifluoromethyl-benzene sulfonyl chloride, obtained the required product of 0.12g.
ESI-MS：413.1[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 11.3 and 11.1 (2s, wide, 1H), 10.55 (m, 1H), 7.9 (d, 2H), 7.55 (d, 2H), 7.2-7.35 (m, 2H), 7.1 (m, 2H), 2.9-3.8 (several m, 7H), 2.3 (m, 1H), 1.8-2.05 (m, 1H), 1.6-1.75 (m, 2H), 0.9 (m, 3H).
Embodiment 9
4-difluoro-methoxy-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use commercially available 4-difluoro-methoxy-benzene sulfonyl chloride, obtained the required product of 0.125g.
ESI-MS：411.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]7.8(d，2H)，7.0-7.2(m，6H)，7.1(m，2H)，6.55(t，1H)，3.25(m，1H)，3.0(m，1H)，2.85(m，1H)，2.65(m，1H)，2.4-2.55(m，3H)，2.25(m，1H)，1.8(m，1H)，1.5(m，2H)，0.9(t，3H)。
Embodiment 10
4-methyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use commercially available 4-methyl-benzene sulfonyl chloride, obtained the required product of 0.31g.
ESI-MS：359.1[M+H] +
1h-NMR (CDCl 3): δ [ppm] 7.7 (m, 1H), 7.2 (m, 1H), 7.05 (m, 1H), 3.3 (m, 1H), 3.0 (m, 1H), 2.85 (m, 1H), 2.65 (m, 1H), 2.2-2.6 (several m, 4H), 2.35 (s, 3H), 1.8 (m, 1H), 1.55 (m, 2H), 0.9 (m, 3H).
Embodiment 11
The chloro-pyridine-3-sulphonic acid of 6-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-acid amides
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use the chloro-pyridine-SULPHURYL CHLORIDE of commercially available 6-, obtained the required product of 0.163g.
ESI-MS：380.1[M+H] +
Embodiment 12
4-methoxyl group-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use commercially available 4-methoxyl group-benzene-SULPHURYL CHLORIDE, obtained the required product of 0.154g.
ESI-MS：375.1[M+H] +
1h-NMR (CDCl 3): δ [ppm] 7.7 (m, 1H), 7.05 (m, 1H), 6.85 (m, 1H), 3.8 (s, 3H), 3.3 (m, 1H), 3.1 (m, 1H), 2.9 (m, 1H), 2.7 (m, 1H), 2.4-2.6 (several m, 3H), 2.3 (m, 1H), 1.8 (m, 1H), 1.55 (m, 2H), 0.9 (m, 3H).
Embodiment 13
The chloro-N-[4-of 4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use the chloro-benzene-SULPHURYL CHLORIDE of commercially available 4-, obtained the required product of 0.175g.
ESI-MS：379.05[M+H] +
1H-NMR(CDCl 3)：δ[ppm]7.7(d，2H)，7.35(d，2H)，7.0-7.2(m，4H)，7.1(m，2H)，3.3(m，1H)，3.05(m，1H)，2.85(m，1H)，2.65(m，1H)，2.4-2.55(m，3H)，2.25(m，1H)，1.8(m，1H)，1.55(m，2H)，0.9(m，3H)。
Embodiment 14
2,3-dihydro-cumarone-5-sulfonic acid [4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-acid amides
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use commercially availablely 2,3-dihydro-cumarone-5-SULPHURYL CHLORIDE, has obtained the required product of 0.207g.
ESI-MS：387.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]7.5-7.6(m，2H)，7.15(m，2H)，6.95(m，2H)，6.7(m，1H)，4.65(m，2H)，3.35(m，1H)，3.2(m，2H)，3.0(m，1H)，2.8(m，1H)，2.6(m，1H)，2.3-2.5(m，3H)，2.2-2.3(m，1H)，1.8(m，1H)，1.5(m，2H)，0.9(m，3H)。
Embodiment 15
The fluoro-N-[4-of the bromo-3-of 4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use the fluoro-benzene-SULPHURYL CHLORIDE of the bromo-3-of commercially available 4-, obtained the required product of 0.289g.
ESI-MS：441.0/443.0[M+H] +
1H-NMR(CDCl 3)：δ[ppm]7.65(m，1H)，7.5(m，1H)，7.4(m，1H)，7.15(d，2H)，7.0(d，2H)，3.3(m，1H)，3.0(m，1H)，2.8(m，1H)，2.65(m，1H)，2.35-2.5(m，3H)，2.3(m，1H)，1.8(m，1H)，1.5(m，2H)，0.9(m，3H)。
Embodiment 16
The fluoro-N-[2-of the bromo-3-of 4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
During the main contraposition product of purifying, can isolate 0.02g ortho position product.
ESI-MS：441.0/443.0[M+H] +
1H-NMR(CDCl 3)：δ[ppm]7.5-7.7(m，3H)，7.1-7.2(m，3H)，7.0(m，1H)，3.5(m，1H)，3.3(m，1H)，3.1-3.2(m，2H)，2.7-2.9(m，3H)，2.3-2.4(m，1H)，1.9-2.1(m，2H)，1.6-1.8(m，2H)，0.9(m，3H)。
Embodiment 17
The fluoro-N-[4-of the bromo-2-of 4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use the fluoro-benzene-SULPHURYL CHLORIDE of the bromo-2-of commercially available 4-, obtained the required product of 0.387g.
ESI-MS：441.0/443.0[M+H] +
1H-NMR(CDCl 3)：δ[ppm]7.65(m，1H)，7.3-7.4(m，2H)，7.15(d，2H)，7.0(d，2H)，3.3(m，1H)，3.0(m，1H)，2.8(m，1H)，2.65(m，1H)，2.35-2.55(m，3H)，2.25(m，1H)，1.75(m，1H)，1.5(m，2H)，0.9(m，3H)。
Embodiment 18
4-sec.-propyl-N-[4-((S)-pyrrolidin-3-yl)-phenyl]-benzsulfamide
By 0.515g4-sec.-propyl-N-[4-((S)-1-allyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide (1.34mmol) is dissolved in 10ml tetrahydrofuran (THF), and under argon gas, be added to 0.049g tri--(dibenzalacetone)-bis-palladiums (0) (0.05mmol) and 0.023g1, in the solution of 4-bis--(diphenylphosphino)-butane (0.05mmol) in 3ml tetrahydrofuran (THF), be then added in the 0.227mg2-Thiosalicylic acid (1.47mmol) in 3ml tetrahydrofuran (THF).By this mixture, stirring at room 2 hours, the solvent was evaporated under reduced pressure, add the water that contains 1N hydrochloric acid with pH regulator to acidic value.By ethyl acetate, water extraction 3 times, then with 1N sodium hydroxide, be adjusted to alkaline pH, by extracted with diethyl ether twice, use twice of dichloromethane extraction.By the organic layer dried over mgso merging, filter, and the solvent was evaporated under reduced pressure, obtained 0.215g secondary amine.
ESI-MS：345.1[M+H] +
Embodiment 19
The fluoro-4-pseudoallyl-N-[4-of 2-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
By the bromo-N-[4-of the fluoro-4-of 0.2g2-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide (0.45mmol), 1.05g tributyl-pseudoallyl-stannane (3.17mmol) and 0.026g tetra-triphenylphosphine palladium (0) (0.02mmol) be dissolved in 3ml tetrahydrofuran (THF), and in 150 ℃, stir 40 minutes in microwave (CEM).This reaction mixture, via diatomite filtration, by methanol wash, and is extremely done filtrate evaporated under reduced pressure.Resistates, by silica gel chromatography purifying, is used to cyclohexane/ethyl acetate (20%), ethyl acetate and ethyl acetate/methanol (15%) wash-out.The level that contains product part is merged, by solvent evaporation, obtained this title product of 0.176g.
ESI-MS：403.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]7.7(m，1H)，7.2-7.3(m，2H)，7.1(m，2H)，7.0(m，2H)，5.45(m，1H)，5.25(m，1H)，3.3-3.4(m，1H)，2.6(m，1H)，2.25-2.35(m，1H)，2.1(s，3H)，1.8-1.9(m，2H)，1.55-1.7(m，3H)，1.2-1.4(m，3H)，0.9(m，3H)。
Embodiment 20
The fluoro-4-pseudoallyl-N-[4-of 3-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
According to prepare the fluoro-4-pseudoallyl-N-[4-of 2-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical method described in-benzsulfamide, from the bromo-N-[4-of the fluoro-4-of 3-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide starts to have obtained the fluoro-4-pseudoallyl-N-[4-of 3-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide, obtain the required product of 0.17g.
ESI-MS：403.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]7.3-7.5(m，3H)，7.15(d，2H)，7.0(d，2H)，5.3(m，2H)，3.35(m，1H)，2.6(m，2H)，2.3(m，1H)，2.1(s，3H)，1.8-1.9(m，2H)，1.55-1.7(m，3H)，1.2-1.4(m，1H)，0.9(m，4H)。
Embodiment 21
The fluoro-4-sec.-propyl-N-[4-of 2-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
By the fluoro-4-pseudoallyl-N-[4-of 0.161g2-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide (0.37mmol) is dissolved in 20ml methyl alcohol, add spoonful sharp 10%Pd/C, and by this reaction mixture in 50 ℃ of hydrogenations 3 hours.This reaction mixture, via diatomite filtration, by methanol wash, and is extremely done filtrate evaporated under reduced pressure.Resistates, by the silica gel chromatography purifying on chromabond post, is used to ethyl acetate and ethyl acetate/methanol (10%) wash-out.The level that contains product part is merged, by solvent evaporation, obtained this title product of 0.11g.
ESI-MS：405.1[M+H] +
1h-NMR (CDCl 3): δ [ppm] 7.7 (m, 1H), 6.9-7.2 (several m, 6H), 3.5-3.6 (m, 2H), 3.2-3.4 (m, 2H), 2.85-3.05 (m, 4H), 2.4 (m, 1H), 2.1 (m, 1H), 1.8 (m, 2H), 1.2 (d, 6H), 0.95 (m, 3H).
Embodiment 22
The fluoro-4-sec.-propyl-N-[4-of 3-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
According to prepare the fluoro-4-sec.-propyl-N-[4-of 2-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical method described in-benzsulfamide, from the fluoro-4-pseudoallyl-N-[4-of 3-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide starts to have obtained the fluoro-4-sec.-propyl-N-[4-of 0.122g3-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide.
ESI-MS：405.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]7.5(m，1H)，7.4(m，1H)，7.3(m，1H)，7.1(d，2H)，7.0(d，2H)，3.4(m，1H)，3.2(m，2H)，3.05(m，1H)，2.9(m，1H)，2.6-2.7(m，3H)，2.1(m，1H)，1.9(m，1H)，1.6-1.7(m，2H)，1.2(d，6H)，0.9(m，3H)。
Embodiment 23
4-isopropoxy-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use commercially available 4-isopropoxy-benzene-SULPHURYL CHLORIDE to obtain the required product of 0.083g.
ESI-MS：403.3[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 11.3 and 11.1 (2s, wide, 1H), 10.2 (m, 1H), 7.7 (d, 2H), 7.25 (m, 1H), 7.2 (m, 1H), 6.95-7.1 (m, 4H), 4.7 (m, 1H), 2.9-3.8 (several m, 7H), 2.3 (m, 1H), 1.85-2.0 (m, 1H), 1.7 (m, 2H), 1.2 (d, 6H), 0.9 (m, 3H).
Embodiment 24
Indane-5-sulfonic acid [4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-acid amides hydrochloric acid
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use commercially available indane-5-SULPHURYL CHLORIDE to obtain the required product of 0.15g.
ESI-MS：385.1[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 11.3 and 11.1 (2s, wide, 1H), 10.25 (m, 1H), 7.6 (s, 1H), 7.5 (d, 1H), 7.35 (d, 1H), 7.25 (m, 1H), 7.2 (m, 1H), 7.05 (m, 2H), 3.2-3.8 (several m, 4H), 2.8-3.1 (several m, 7H), 2.3 (m, 1H), 1.8-2.05 (m, 3H), 1.6-1.7 (m, 2H), 0.9 (m, 3H).
Embodiment 25
The bromo-N-[4-of 4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use the bromo-benzene-SULPHURYL CHLORIDE of commercially available 4-, obtained the required product of 0.07g.
ESI-MS：425.0[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 11.3 and 11.05 (2s, wide, 1H), 10.45 (m, 1H), 7.8 (d, 2H), 7.7 (d, 2H), 7.3 (m, 1H), 7.2 (m, 1H), 7.05 (m, 2H), 2.9-3.8 (several m, 7H), 2.3 (m, 1H), 1.85-2.05 (m, 1H), 1.6-1.8 (m, 2H), 0.9 (m, 3H).
Embodiment 26
4-ethanoyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide, use commercially available 4-ethanoyl-benzene-SULPHURYL CHLORIDE, obtained the required product of 0.159g.
ESI-MS：387.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]8.0(d，2H)，7.8(d，2H)，7.15(d，2H)，6.95(d，2H)，3.3(m，1H)，3.0(m，1H)，2.8(m，1H)，2.65(m，1H)，2.6(s，3H)，2.35-2.5(m，3H)，2.25(m，1H)，1.8(m，1H)，1.5(m，2H)，0.9(m，3H)。
Embodiment 27
4-cyclopropyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
By the bromo-N-[4-of 0.3g4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide (0.71mmol), 0.079g cyclopropylboronic acid (0.92mmol), 0.526g potassiumphosphate (2.48mmol) and 0.02g tricyclohexyl phosphine be dissolved in the mixture of 4ml toluene and 2ml water.After adding 0.008g acid chloride (II) (0.04mmol), this reaction is stirred 1 hour in 100 ℃ in microwave (CEM).By this solution decant, the remaining suspension liquid that contains catalyzer, again with ethyl acetate washing, is evaporated to the solvent extraction liquid of merging dry, then be dissolved in ethyl acetate, and wash with water.Water is extracted once by ethyl acetate again, merge organic layer, by dried over mgso, filter and reduction vaporization.Crude product, by silica gel chromatography purifying, is used to methylene dichloride, methylene chloride-methanol (5.5%) wash-out.The level that contains product part is merged, except desolventizing, obtained this title product of 0.066g.
ESI-MS：385.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]7.65(d，2H)，6.95-7.15(m，6H)，3.3(m，1H)，3.1(m，1H)，2.9(m，1H)，2.75(m，1H)，2.5(m，3H)，2.35(m，1H)，2.0(m，1H)，1.8(m，2H)，1.55(m，2H)，1.25(m，1H)，1.0(m，1H)，0.9(m，3H)，0.7(m，1H)。
Embodiment 28
Bromo-thiophene-the 2-of 5-sulfonic acid [4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-acid amides hydrochloric acid
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use the bromo-thiophene-2-of commercially available 5-SULPHURYL CHLORIDE, obtained this title product of 0.05g.
ESI-MS：431.0[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 11.2 and 11.0 (2s, wide, 1H), 10.65 (m, 1H), 7.2-7.4 (several m, 4H), 7.1 (m, 2H), 3.0-3.8 (several m, 7H), 2.3 (m, 1H), 1.85-2.0 (m, 1H), 1.7 (m, 2H), 0.9 (m, 3H).
Embodiment 29
5-pseudoallyl-thiophene-2-sulfonic acid [4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-acid amides
According to prepare the fluoro-4-pseudoallyl-N-[4-of 2-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical method described in-benzsulfamide, from the bromo-thiophene-2-of 5-sulfonic acid [4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-acid amides, start to have obtained this title product of 0.154g.
ESI-MS：391.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]7.3(m，1H)，7.25(m，1H)，7.2(d，2H)，7.05(d，2H)，6.9(m，1H)，5.4(s，1H)，5.1(s，1H)，3.3(m，1H)，3.05(m，1H)，2.9(m，1H)，2.7(m，1H)，2.5(m，2H)，2.3(m，1H)，2.05(s，3H)，1.85(m，1H)，1.6(m，2H)，1.3(m，1H)，0.9(m，3H)。
Embodiment 30
4-propyl group-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use commercially available 4-propyl group-benzene-SULPHURYL CHLORIDE, obtained this title product of 0.037g.
ESI-MS：387.2[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 10.3 (m, 1H), 7.7 (d, 2H), 7.3 (d, 2H), 7.25 (m, 1H), 7.2 (m, 1H), 7.05 (m, 2H), 2.9-3.8 (several m, 7H), 2.55 (m, 2H), 2.3 (m, 1H), 1.85-2.0 (m, 1H), 1.7 (m, 2H), 1.55 (m, 2H), 0.9 (m, 3H), 0.8 (m, 3H).
Embodiment 31
N-[6-(1-propyl group-pyrrolidin-3-yl)-pyridin-3-yl]-4-sec.-propyl-benzene-sulphonamide
31.1 5-nitro-2-vinyl-pyridines
The chloro-5-nitro-pyridine of 0.5g2-(3.15mmol), 1.2g tributyl-vinyl-stannane (3.78mmol), 0.036g tetra-triphenylphosphine palladium (0) (0.03mmol) are dissolved in 20ml toluene with 0.024g triphenylphosphine (0.09mmol), and stir 2 hours under refluxing.Be cooled to after room temperature, add 10ml water, water layer is extracted with ethyl acetate, and the organic layer of merging is washed with saturated sodium-chloride, by dried over mgso, filter, and the solvent was evaporated under reduced pressure.Crude product, via silica gel chromatography purifying, is used to cyclohexane/ethyl acetate (10%) wash-out.The level that contains product part is merged, by solvent evaporation, obtained the required product of 0.528g.
ESI-MS：151.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]9.4(s，1H)，8.4(m，1H)，7.45(m，1H)，6.9(q，1H)，6.45(m，1H)，5.7(m，1H)。
31.2 2-(1-benzyl-pyrrolidin-3-yl)-5-nitro-pyridine
0.15g5-nitro-2-vinyl-pyridine is dissolved in 2.5ml methylene dichloride, add 0.149g trifluoroacetic acid (1.31mmol), then add lentamente 0.928g N-benzyl-N-(methoxymethyl)-N-trimethyl silyl methylamine (3.91mmol).In room temperature, continue to stir 1 hour, then this reaction mixture is washed with sodium bicarbonate aqueous solution, water layer is extracted with methylene dichloride again, merge organic layer, by dried over mgso, filter, and the solvent was evaporated under reduced pressure.Crude product, via silica gel chromatography purifying, is used to eluent ethyl acetate.The level that contains product part is merged, by solvent evaporation, obtained the required product of 0.186g.
ESI-MS：284.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]9.25(m，1H)，8.3(m，1H)，7.4(m，1H)，7.15-7.3(m，5H)，3.6(d，2H)，3.55(m，1H)，2.9(m，1H)，2.7(m，2H)，2.65(m，1H)，2.3(m，1H)，2.0(m，1H)。
31.3 2-(1-benzyl-pyrrolidin-3-yl)-5-amino-pyridine
0.181g2-(1-benzyl-pyrrolidin-3-yl)-5-nitro-pyridine is dissolved in 10ml methyl alcohol, adds 1.15g tindichloride SnCl in batches 2(5.11mmol).Continue under reflux conditions to stir 1 hour.By solvent evaporation, resistates is processed by 1N aqueous sodium hydroxide solution and ethyl acetate, and filtered.Isolate two layers, water is extracted with ethyl acetate to twice, and by the organic layer dried over mgso merging, filter, and the solvent was evaporated under reduced pressure, obtained the amino crude product of 0.191g, it need not be further purified and be directly used in next reaction.
ESI-MS：254.1[M+H] +
31.4 N-[6-(1-benzyl-pyrrolidin-3-yl)-pyridin-3-yl]-4-sec.-propyl-benzene-sulphonamide
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use commercially available 4-propyl group-benzene-SULPHURYL CHLORIDE to obtain the required product of 0.12g.By the silica gel chromatography purification of crude product on cromabond post, use ethyl acetate as eluent.
ESI-MS：436.1[M+H] +
31.5 N-[6-(pyrrolidin-3-yl)-pyridin-3-yl]-4-sec.-propyl-benzene-sulphonamide
By 0.12g N-[6-(1-benzyl-pyrrolidin-3-yl)-pyridin-3-yl]-4-sec.-propyl-benzene-sulphonamide (0.28mmol) is dissolved in 20ml methyl alcohol, add spoonful sharp 10%Pd/C, and by this reaction mixture room temperature hydrogenation 2 hours, 50 ℃ of hydrogenations 4 hours.By removing by filter catalyzer, and filtrate is evaporated to dry, has obtained the required benzyl compound that goes of 0.088g.
ESI-MS：346.1[M+H] +
31.6 N-[6-(1-propyl group-pyrrolidin-3-yl)-pyridin-3-yl]-4-sec.-propyl-benzene-sulphonamide is 0.088gN-[6-(1-benzyl-pyrrolidin-3-yl)-pyridin-3-yl]-4-sec.-propyl-benzene-sulphonamide (0.25mmol) is dissolved in 10ml methylene dichloride.Add 0.022g propionic aldehyde (0.38mmol), 0.023g acetic acid (0.38mmol) and 0.081g sodium triacetoxy borohydride (0.38mmol), and stirring at room 1 hour.Add water, with 1N sodium hydroxide, by pH regulator to 10, be extracted with ethyl acetate 3 times, organic layer is merged, and be evaporated to dry.Crude product, by silica gel chromatography purifying, is used to methylene chloride/methanol 20% wash-out.The level that contains product part is merged and by solvent evaporation, obtained 0.026mg product.
ESI-MS：388.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]8.15(m，1H)，7.7(d，2H)，7.5(m，1H)，7.3(d，2H)，7.1(m，1H)，3.5(m，1H)，3.2(m，1H)，2.95(m，2H)，2.75(m，2H)，2.5-2.65(m，2H)，2.3(m，1H)，2.0(m，1H)，1.6(m，2H)，1.2(m，6H)，0.9(m，3H)。
Embodiment 32
4-dimethylaminomethyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
32.1 4-formyl radical-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide, use commercially available 4-formyl radical-benzene-SULPHURYL CHLORIDE, obtained the required product of 0.584g.Product need not be further purified and be directly used in next step.
ESI-MS：373.4[M+H] +
32.2 4-dimethylaminomethyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
By 0.3g4-formyl radical-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide (0.81mmol) is dissolved in 20ml methylene dichloride; add the solution (1.21mmol) of 0.6ml2M dimethyl amine in tetrahydrofuran (THF), then add 0.07ml acetic acid and 0.256g sodium triacetoxy borohydride.This reaction, stirring at room 15 hours, is added to water, with 1N aqueous sodium hydroxide solution pH regulator to alkaline condition, by twice of extracted with diethyl ether for water layer.By the ether extraction liquid dried over mgso merging, filtration and the solvent was evaporated under reduced pressure.On 40mm Deltapak post, by preparative HPLC, carry out purification of crude product, with methanol/water/0.1% acetic acid wash-out.The level that contains product part is merged, by solvent evaporation, extract after alkaline water layer, isolated product (0.051g).
ESI-MS：402.1[M+H] +
Embodiment 33
4-sec-butyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use commercially available 4-sec-butyl-benzene sulfonyl chloride (ART-Chem), obtained the required product of 0.082g.
ESI-MS：401.1[M+H] +
Embodiment 34
4-is bromo-3, the fluoro-N-[4-of 6-bis-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide, use commercially available 4-bromo-3, the fluoro-benzene sulfonyl chloride of 6-bis-, has obtained the required product of 0.131g.
ESI-MS：459.0/461.0[M+H] +
1h-NMR (CDCl 3): δ [ppm] 7.55 (m, 1H), 7.4 (m, 1H), 7.15 (d, 2H), 7.0 (d, 2H), 4.7 (s, non-constant widths, 2H), 3.3 (m, 1H), 3.0 (m, 1H), 2.85 (m, 1H), 2.7 (m, 1H), 2.4-2.6 (m, 3H), 2.25 (m, 1H), 1.8 (m, 1H), 1.55 (m, 2H), 0.85 (m, 3H).
Embodiment 35
4-isobutyl--N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide hydrochloride, use commercially available 4-isobutyl--benzene sulfonyl chloride, obtained the required product of 0.164g.
ESI-MS：401.1[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 11.3 and 11.1 (2s, wide, 1H), 10.3 (m, 1H), 7.7 (d, 2H), 7.3 (d, 2H), 7.25 (m, 1H), 7.2 (m, 1H), 7.05 (m, 2H), 2.9-3.8 (several m, 9H), 2.3 (m, 1H), 1.8-2.0 (m, 2H), 1.7 (m, 2H), 0.9 (m, 3H), 0.8 (m, 6H).
Embodiment 36
4-carboxy-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide, use commercially available 4-carboxyl-benzene sulfonyl chloride, obtained the required product of 0.105g.From water layer, by filtering, stir together with methyl alcohol, again filter and be dried, finally isolated the product as precipitation.
ESI-MS：389.1[M+H] +
1h-NMR (DMSO-d 6): δ [ppm] 10.25 (s, 1H), 9.6 (s, wide, 1H), 7.9 (d, 2H), 7.7-7.8 (m, 4H), 7.3 (d, 2H), 3.0-3.9 (several wide m, 7H), 2.4 (m, 1H), 2.0 (m, 1H), 1.7 (m, 2H), 0.9 (m, 3H).
Embodiment 37
4-cyclopentyl-N-[4-(S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
By the bromo-N-[4-of 0.278g4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide (0.66mmol) is dissolved in 5ml tetrahydrofuran (THF).Add 0.027g1,1 '-bis-(diphenylphosphino) ferrocene (dppf) PdCl 2(0.03mmol) with 0.008g CuI (0.04mmol), then drip the solution of the commercially available 0.5M brominated amyl group zinc of 2ml in tetrahydrofuran (THF).Stirring at room 15 hours and add again after brominated amyl group zinc, this reaction mixture is processed by ethyl acetate, wash with water, and organic layer, via diatomite filtration, with ethyl acetate washing, is washed with water, and by organic layer dried over mgso, filter and removal of solvent under reduced pressure.By preparative HPLC (Delta Pakcolumn, 40mm diameter) purifying, use methanol/water/0.1% acetic acid as eluent crude product.The level that contains product part is merged, remove methyl alcohol, add 0.2ml 1N hydrochloric acid, water layer lyophilize, obtained 0.0107g product.
ESI-MS：413.1[M+H] +
1h-NMR (CDCl 3): δ [ppm] 12.4 & 12.3 (2s, wide, 1H), 7.7-7.9 (m, 3H), 7.25 (m, 2H), 7.0-7.2 (m, 3H), 4.0 (m, wide, 2H), 3.75 (m, wide, 1H), and 2.5-3.0 (several m are wide, 6H), and 2.35 (m, wide, 1H), 1.5-2.1 (several m, wide, 10H), 1.0 (m, wide, 3H).
Embodiment 38
4-sec.-propyl-N-[4-((S)-1-(the fluoro-propyl group of 3-)-pyrrolidin-3-yl)-phenyl]-benzsulfamide
By 0.215g4-sec.-propyl-N-[4-((S)-pyrrolidin-3-yl)-phenyl]-benzsulfamide (0.0.62mmol) and the fluoro-propyl diester of 0.16g toluene-4-sulfonic acid 3-(0.69mmol) be dissolved in 5ml dimethyl formamide, add 0.43ml triethylamine, and this reaction is stirred 1 hour at 50 ℃.Add again the fluoro-propyl diester of toluene-4-sulfonic acid 3-and triethylamine to react completely to drive.In stirring at room, after 15 hours, by solvent evaporation, resistates is dissolved in methylene dichloride again, and organic layer is washed by 1N aqueous sodium hydroxide washes.By dichloromethane extraction twice for water, merge organic layer, by dried over mgso, filter and solvent is evaporated.Crude product, via silica gel chromatography purifying (chromabond post), is used to methylene chloride/methanol 0-3% wash-out.The level that collection contains product part and by solvent evaporation, has obtained the required product of 0.115g.
ESI-MS：405.1[M+H] +
1h-NMR (CDCl 3, 400MHz): δ [ppm] 7.7 (d, 2H), 7.3 (d, 2H), 7.15 (d, 2H), 7.0 (d, 2H), 4.6 (m, 1H), 4.45 (m, 1H), 3.3 (m, 1H), 2.95 (m, 2H), 2.8 (m, 1H), 2.5-2.7 (several m, 3H), 2,45 (m, 1H), 2.25 (m, 1H), 1.75-2.0 (several m, 3H), 1.2 (m, 6H).
Embodiment 39
3-trifluoromethyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide, use commercially available 3-trifluoromethyl-benzene sulfonyl chloride, obtained the required product of 0.11g.
ESI-MS：427.2[M+H] +
Embodiment 40
4-butoxy-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide, use commercially available 4-butoxy-benzene sulfonyl chloride, obtained required product.
ESI-MS：417.3[M+H] +
1h-NMR (CDCl 3, 400MHz): δ [ppm] 7.7 (d, 2H), 7.15 (d, 2H), 6.95 (d, 2H), 6.85 (d, 2H), 5.6 (s, wide, 1H), 3.95 (t, 2H), 3.3 (m, 1H), 3.0 (m, 1H), 2.8 (m, 1H), 2.6 (m, 1H), 2.45 (m, 1H), 2.35 (m, 2H), 2.25 (m, 1H), 1.75 (m, 3H), 1.5 (m, 4H), 0.96 (m, 6H).
Embodiment 41
4-(2,2-difluoro cyclopropyl)-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
According to preparation 4-sec.-propyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] identical synthetic method described in-benzsulfamide, use 4-(the fluoro-cyclopropyl of 2,2-bis-)-benzene sulfonyl chloride, obtained required product.
ESI-MS：421.15[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.75(d，2H)，7.25(d，2H)，7.15(d，2H)，7.0(d，2H)，5.65(bs，1H)，3.3(m，1H)，3.05(m，1H)，2.85(m，1H)，2.75(m，1H)，2.65(m，1H)，2.45(m，3H)，2.3(m，1H)，1.9(m，1H)，1.8(m，1H)，1.65(m，1H)，1.55(m，2H)，0.95(t，3H)。
embodiment 42
N-[3-(1-propyl group-pyrrolidin-3-yl)-phenyl]-4-trifluoromethoxy-benzsulfamide * HCl
42.1 3-[3-(4-trifluoromethoxy-benzenesulfonyl is amino)-phenyl]-tetramethyleneimine-1-methyl-formiate
At 10 ℃, to 3-(3-amino-phenyl)-tetramethyleneimine-1-methyl-formiate (500mg, 2.27mmol) and in the solution of triethylamine (500mg, 4.94mmol) in THF (20ml) add 4-trifluoromethoxy-benzene sulfonyl chloride (600mg, 2.3mmol).Allow this mixture arrive room temperature, and stir 16 hours.This mixture is poured in water, and be extracted with ethyl acetate 3 times.By organic layer water and saturated nacl aqueous solution washing, with dried over mgso and reduction vaporization, obtained product, be brown oil (1g, 99%).
42.2 N-(3-pyrrolidin-3-yl-phenyl)-4-trifluoromethoxy-benzsulfamide
By 3-[3-(4-trifluoromethoxy-benzenesulfonyl amino)-phenyl]-tetramethyleneimine-1-methyl-formiate (500mg, 1.13mmol) and HCl (8M, 137.82mmol) reflux 48 hours in EtOH (10ml).This mixture is extracted with ethyl acetate to twice, then adds NaOH (2M).Water is extracted with ethyl acetate twice.By the organic layer water merging and saturated nacl aqueous solution washing, with dried over mgso and reduction vaporization, obtained product, be brown oil (200mg, 46%).
42.3 N-[3-(1-propyl group-pyrrolidin-3-yl)-phenyl]-4-trifluoromethoxy-benzsulfamide * HCl
By N-(3-pyrrolidin-3-yl-phenyl)-4-trifluoromethoxy-benzsulfamide (200mg, 0.52mmol), acetic acid (30 μ l, 0.52mmol) and propionic aldehyde (30mg, 0.52mmol) solution in methylene dichloride (20ml) was in stirring at room 30 minutes, then at 15 ℃, add sodium triacetoxy borohydride (165mg, 0.78mmol) in batches.By this mixture stirring at room 16 hours.This mixture is poured in water/methylene dichloride (1/1), organic layer is washed with water, with dried over mgso and reduction vaporization.By column chromatography purifying resistates (CH 2cl 2/ methyl alcohol-2%, 3%, 4%, 6%), obtained brown oil.In this oily matter, adding the diethyl ether solution (1M) of ether HCl, and by this mixture reduction vaporization, obtained product, is white foam shape thing, by its vacuum-drying (55mg, 23%).
MS(ESI)m/z：429.15[M+H] +
1H-NMR(DMSO-d 6)：δ[ppm]11.0-11.2(m，1H)，10.6(s，1H)，7.90-7.95(m，2H)，7.60-7.65(m，2H)，7.20-7.25(m，1H)，6.95-7.10(m，3H)，3.35-3.80(m，3H)，3.20-3.30(m，1H)，3.05-3.15(m，2H)，2.90-3.05(m，1H)，2.25-2.35(m，1H)，1.85-2.05(m，1H)，1.65-1.80(m，2H)，0.90-1.00(m，3H)。
embodiment 43
4-sec.-propyl-N-[3-(1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide * HCl
43.1 3-[3-(4-sec.-propyl-benzenesulfonyl is amino)-phenyl]-tetramethyleneimine-1-methyl-formiate
To 3-(3-amino-phenyl)-tetramethyleneimine-1-methyl-formiate (500mg, 2.27mmol) and triethylamine (500mg, 4.94mmol) in the solution in THF (20ml), in 10 ℃, add 4-sec.-propyl-benzene sulfonyl chloride (500mg, 2.27mmol).Allow this mixture arrive room temperature and to stir 16 hours.This mixture is poured in water, and be extracted with ethyl acetate 3 times.By organic layer water and saturated nacl aqueous solution washing, with dried over mgso and reduction vaporization, obtained product, be brown oil (1g, 100%).
43.2 4-sec.-propyl-N-(3-pyrrolidin-3-yl-phenyl)-benzsulfamide
By 3-[3-(4-sec.-propyl-benzenesulfonyl amino)-phenyl]-tetramethyleneimine-1-methyl-formiate (900mg, 1.13mmol) and the mixture of HCl (8M, 273.90mmol) in EtOH (20ml) be heated to reflux 48 hours.This mixture is extracted with ethyl acetate to twice, then adds NaOH (2M).Water is extracted with ethyl acetate twice.By the organic layer water merging and saturated nacl aqueous solution washing, with dried over mgso and reduction vaporization, obtained product, be brown oil (100mg, 13%).
43.3 4-sec.-propyl-N-[3-(1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide * HCl
By 4-sec.-propyl-N-(3-pyrrolidin-3-yl-phenyl)-benzsulfamide (100mg, 0.29mmol), acetic acid (20 μ l, 0.29mmol) and propionic aldehyde (16.86mg, 0.29mmol) solution in methylene dichloride (20ml) was in stirring at room 30 minutes, then in room temperature, add sodium triacetoxy borohydride (123mg, 0.58mmol) in batches.By this mixture in stirring at room 16 hours.This mixture is poured into saturated NaHCO 3in the aqueous solution/methylene dichloride (1/1), and by organic layer water and saturated nacl aqueous solution washing, with dried over mgso and reduction vaporization.By column chromatography purifying resistates (CH 2cl 2/ methyl alcohol-2%, 4%, 6%).In solution to the product of purifying in ether, adding the solution of HCl in ether (1M), and by this mixture reduction vaporization, obtained product, is white foam shape thing, by its vacuum-drying (55mg, 45%).
MS(ESI)m/z：387.15[M+H] +
1H-NMR(CDCl 3)：δ[ppm]8.95-9.15-(m，1H)，7.72-7.82(m，2H)，6.85-7.31(m，6H)，3.85-4.05(m，1H)，3.65-3.79(m，1H)，3.25-3.56(m，1H)，3.0-3.2(m，2H)，2.78-3.0(m，2H)，2.43-2.55(m，1H)，1.80-2.40(m，5H)，1.12-1.21(m，6H)，0.9-1.02(m，3H)。
embodiment 44
N-[3-(1-cyclopropyl methyl-pyrrolidin-3-yl)-phenyl]-4-sec.-propyl-benzsulfamide x HCl
By 4-sec.-propyl-N-(3-pyrrolidin-3-yl-phenyl)-benzsulfamide (100mg, 0.29mmol), acetic acid (20 μ l, 0.29mmol) and cyclopanecarboxaldehyde (20.35mg, 0.29mmol) mixture in methylene dichloride (20ml) was in stirring at room 30 minutes, then spread out and add sodium triacetoxy borohydride (123mg, 0.58mmol) in room temperature in batches.By this mixture stirring at room 16 hours.This mixture is poured into saturated NaHCO 3in the aqueous solution/methylene dichloride (1/1), and by organic layer water and saturated nacl aqueous solution washing, with dried over mgso and reduction vaporization.By column chromatography purifying resistates (CH 2cl 2/ methyl alcohol-2%, 4%, 6%).In solution to the product of purifying in ether, adding the solution of HCl in ether (1M), and by this mixture reduction vaporization, obtained product, is brown foam, by its vacuum-drying (50mg, 40%).
MS(ESI)m/z：399.25[M+H] +
1H-NMR(CDCl 3)：δ[ppm]9.05-9.35-(m，1H)，7.72-7.81(m，2H)，6.82-7.35(m，6H)，3.69-4.05(m，2H)，2.70-3.25(m，5H)，2.0-2.55(m，3H)，1.1-1.3(m，7H)，0.6-0.8(m，2H)，0.47-0.5(m，2H)。
Embodiment 45
N-[3-(1-allyl group-pyrrolidin-3-yl)-phenyl]-4-sec.-propyl-benzsulfamide x HCl
By 4-sec.-propyl-N-(3-pyrrolidin-3-yl-phenyl)-benzsulfamide (100mg, 0.29mmol), allyl bromide 98 (38mg, 0.31mmol), salt of wormwood (60mg, 0.43mmol) and the solution of Potassium monofluoride (0.2mg, 0.003mmol) in acetone (20ml) be heated to reflux 4 hours.This mixture reduction vaporization, and resistates is distributed between ethyl acetate and water.Organic layer is washed with saturated nacl aqueous solution, with dried over mgso and reduction vaporization.By column chromatography purifying resistates (CH 2cl 2/ methyl alcohol-2%, 4%, 6%).In solution to the product of purifying in methylene dichloride, adding the solution of HCl in ether (1M), and by this mixture reduction vaporization, obtained product, is brown foam, by its vacuum-drying (25mg, 21%).
MS(ESI)m/z：385.15[M+H] +
1H-NMR(CDCl 3)：δ[ppm]8.79-8.95-(m，1H)，7.72-7.81(m，2H)，6.85-7.30(m，6H)，6.05-6.20(m，1H)，5.43-5.56(m，2H)，3.10-3.95(m，6H)，2.80-2.95(m，1H)，1.90-2.55(m，3H)，1.15-1.25(m，6H)。
Embodiment 46
4-sec.-propyl-N-[6-(1-propyl group-azetidine-3-yl)-pyridin-3-yl]-benzsulfamide
46.1 3-hydroxyl-azetidine-1-formic acid tertiary butyl ester
To degassed 1-diphenyl-methyl-aza-cyclobutane-3-alcohol (4.75g, 19.84mmol), at methyl alcohol (methyl alcohol), in the solution in (150ml), add ammonium formiate (8.76g, 138.91mmol), 10%Pd/C (450mg) and Boc 2o (tert-Butyl dicarbonate) (13g, 59.56mmol).By gained suspension at N 2under be heated to reflux 1 hour.Then be cooled to room temperature, by short Celite pad, filter and concentrate.Resistates is dissolved in to CH 2cl 2in and wash with water.By the dry (Na of organic layer 2sO 4) and evaporation.By crude product with silica gel column chromatography purify (heptane: ethyl acetate (ethyl acetate), 1:1), obtain this title compound (3.30g, 96%), be white crystal.
MS(ESI+)m/z＝118.1[M-tBu+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)1.43(s，9H)，2.35(d，J＝6.2Hz，IH)，3.80(dd，J＝10.4，4.4Hz，2H)，4.15(dd，J＝9.6，6.7Hz，2H)，4.58(m，1H)。
Iodo-azetidine-the 1-of 46.2 3-formic acid tertiary butyl ester
Imidazoles for solution (3.95g, 58.01mmol) 3-hydroxyl-azetidine-1-formic acid tertiary butyl ester (3.35g, 19.34mmol) in toluene (200ml), triphenylphosphine (10.14g, 38.65mmol) and I 2(7.36g, 28.99mmol) processes.This mixture, at 100 ℃ of heating 1h, is cooled to room temperature, then pours saturated NaHCO into 3in solution (30ml).By adding iodine to destroy excessive triphenylphosphine until the I in organic layer 2color continues.By the latter 5%Na 2s 2o 3solution washing, uses Na 2sO 4be dried and evaporate.By crude product by flash column chromatography purifying (heptane: ethyl acetate, 2:1), obtain this title compound (5.19g, 95%), be light yellow oil.
MS(ESI+)m/z＝227.9[M-tBu+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)1.44(s，9H)，4.29(dd，J＝10.4，5.4Hz，2H)，4.47(m，1H)，4.64(dd，J＝9.5，8.0Hz，2H)。
46.3 3-(5-nitro-pyridine-2-yl)-azetidine-1-formic acid tertiary butyl ester
By Zn powder (520mg, 7.95mmol) in THF (2ml) under nitrogen vigorous stirring, and add 1,2-ethylene dichloride (84 μ l, 0.97mmol).Then this suspension is heated 8 minutes at 80 ℃, be then cooled to room temperature.Then add the solution of trimethylsilyl chloride (115 μ l, 0.92mmol) in THF (1ml), and this mixture is further stirred 45 minutes in room temperature.Then the solution in THF (2ml) is added drop-wise in this solution 3-iodo-azetidine-1-formic acid tertiary butyl ester (1.74g, 6.14mmol) to use 15 minutes, and by this reaction mixture stirring at room 2 hours.Then Pd 2(dba) 3(90mg, 0.10mmol) and P (2-furyl) 3(85mg, 0.36mmol) is added in this mixture, then adds the solution of the bromo-5-nitropyridine of 2-(1.37g, 6.74mmol) in THF (4ml).Then this mixture is heated 3 hours at 55 ℃, be cooled to room temperature and end with the saturated NaCl aqueous solution.Use CH 2cl 2extraction, by the dry (Na of organic phase 2sO 4), filter and vacuum-evaporation, obtain rough material, passed through flash column chromatography purifying (heptane: ethyl acetate, 3:1), obtained this title compound (1.22g, 71%), be light yellow oil.
MS(ESI+)m/z＝224.1[M-tBu+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)1.47(s，9H)，3.99(m，1H)，4.18(dd，J＝8.2，6.1Hz，2H)，4.35(t，J＝8.6Hz，2H)，7.42(d，J＝8.5Hz，1H)，8.45(dd，J＝8.5，2.6Hz，1H)，9.44(d，J＝2.4Hz，1H)。
46.4 1-[3-(5-nitro-pyridine-2-yl)-azetidine-1-yl]-propyl-1-ketone
By 3-(5-nitro-pyridine-2-yl)-azetidine-1-formic acid tertiary butyl ester (1.22g, 4.36mmol) at CH 2cl 2(100ml) trifluoroacetic acid for solution (TFA) in (15ml) is processed, then in stirring at room 2 hours.After concentrated, by this crude mixture at CH 2cl 2middle boiling, and use NaHCO 3solution washing.By organic phase CH 2cl 2(* 3) extraction, by the organic layer Na of merging 2sO 4be dried and evaporate.Then crude product is dissolved in THF (80ml), and this solution is cooled to 0 ℃.Add propionyl chloride (460 μ l, 5.26mmol) and triethylamine (735 μ l, 5.28mmol), this mixture is warming up to 20 ℃, and stirs other 12 hours.Then used CH 2cl 2dilution, and in succession use the 1N HCl aqueous solution, saturated NaHCO 3the aqueous solution and water washing.By the dry (Na of organic layer 2sO 4) and evaporation.Resistates is carried out to silica gel chromatography purifying (CH 2cl 2: methyl alcohol, 49:1), obtain this title compound (880mg, 85% liang of step), be brown oil.
MS(ESI+)m/z＝236.1[M+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)1.16(t，J＝7.5Hz，3H)，2.18(q，J＝7.5Hz，2H)，4.07(m，1H)，4.22(dd，J＝9.5，6.0Hz，1H)，4.44(m，2H)，4.52(t，J＝8.4Hz，1H)，7.42(d，J＝8.5Hz，1H)，8.46(dd，J＝8.5，2.6Hz，1H)，9.45(d，J＝2.5Hz，1H)。
46.5 4-sec.-propyl-N-[6-(1-propionyl-azetidine-3-yl)-pyridin-3-yl]-benzsulfamide
1-[3-(5-nitro-pyridine-2-yl)-azetidine-1-yl]-propyl-1-ketone (340mg, 1.44mmol) be dissolved in ethanol (EtOH) (25ml) in, and add SnCl 2.2H 2o (1.63g, 7.22mmol).By gained mixture backflow 8h, and under vacuum, remove desolventizing.Crude product is dissolved in ethyl acetate, and in succession uses 2N NaOH (x2) aqueous solution and water washing.By the dry (Na of organic layer 2sO 4), by Celite pad, filter and evaporate.Half of this rough material is dissolved in to CH 2cl 2(40ml) and in pyridine (115 μ l, 1.41mmol), then drip 4-isopropyl benzene SULPHURYL CHLORIDE (190 μ l, 1.05mmol).After stirred overnight at room temperature, by this reaction mixture CH 2cl 2hour, and in succession use 1N HCl, saturated NaHCO 3the aqueous solution and water washing.By the dry (Na of organic layer 2sO 4) and evaporation.By resistates carry out silica gel chromatography purifying (heptane: ethyl acetate, 1:3), obtain this title compound (150mg, 54% liang of step), be light yellow oil.
MS(ESI+)m/z＝388.1[M+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)1.14(t，J＝7.5Hz，3H)，1.24(d，J＝6.9Hz，6H)，2.14(q，J＝7.5Hz，2H)，2.94(m，1H)，3.87(m，1H)，4.10(dd，J＝9.7，5.9Hz，1H)，4.34(m，2H)，4.42(t，J＝8.5Hz，1H)，7.12(d，J＝8.4Hz，1H)，7.31(m，3H)，7.59(dd，J＝8.4，2.6Hz，1H)，7.71(d，J＝8.4Hz，2H)，8.25(d，J＝2.3Hz，1H)。
46.6 4-sec.-propyl-N-[6-(1-propyl group-azetidine-3-yl)-pyridin-3-yl]-benzsulfamide
To 4-sec.-propyl-N-[6-(1-propionyl-azetidine-3-yl)-pyridin-3-yl] in the solution of-benzsulfamide (150mg, 0.38mmol) in THF (15ml), drip 1M BH 3.THF (3.8ml), and this mixture derivant is stirred 12 hours.Then by the careful 1N of the adding HCl aqueous solution (10ml), ended, and gained solution is heated 4 hours under refluxing.This solution is cooled to room temperature, with 2NNaOH solution, is adjusted to pH～8, and use CH 2cl 2dilution.Layer is separated, by the dry (Na of organic phase 2sO 4), filter and vacuum-evaporation, obtain rough material, passed through flash column chromatography purifying (CH 2cl 2: methyl alcohol, 95:5), obtained this title compound (95mg, 66%), be light yellow oil.
MS(ESI+)m/z＝374.1[M+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)0.93(t，J＝7.4Hz，3H)，1.24(d，J＝6.9Hz，6H)，1.47(m，2H)，2.62(m，2H)，2.94(m，1H)，3.44(m，2H)，3.90(m，3H)，7.15(d，J＝8.4Hz，1H)，7.31(d，J＝8.3Hz，2H)，7.52(dd，J＝8.4，2.6Hz，1H)，7.70(d，J＝8.3Hz，2H)，8.22(d，J＝1.8Hz，1H)。
Embodiment 47
N-[6-(1-propyl group-azetidine-3-yl)-pyridin-3-yl]-4-trifluoromethoxy-benzsulfamide
47.1 N-[6-(1-propionyl-azetidine-3-yl)-pyridin-3-yl]-4-trifluoromethoxy-benzsulfamide
According to above-mentioned same method, by second half of the aminopyridine obtaining in 46.5 with pyridine (115 μ l, 1.41mmol) and 4-(trifluoromethoxy) benzene sulfonyl chloride (180 μ l, 1.06mmol) at CH 2cl 2(40ml) mixture process in.By flash column chromatography purifying (heptane: ethyl acetate, 1:2).Having obtained this title compound (130mg, 42% liang of step), is light yellow oil.
MS(ESI+)m/z＝430.0[M+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)1.14(t，J＝7.5Hz，3H)，2.16(q，J＝7.5Hz，2H)，3.86(m，1H)，4.08(dd，J＝9.5，6.1Hz，1H)，4.34(m，2H)，4.43(t，J＝8.4Hz，1H)，7.12(d，J＝8.4Hz，1H)，7.29(d，J＝8.3Hz，2H)，7.60(dd，J＝8.4，2.6Hz，1H)，7.87(d，J＝8.9Hz，2H)，8.01(bs，1H)，8.28(d，J＝2.0Hz，1H)。
47.2 N-[6-(1-propyl group-azetidine-3-yl)-pyridin-3-yl]-4-trifluoromethoxy-benzsulfamide
According to the same method of describing in embodiment 46.6, by N-[6-(1-propionyl-azetidine-3-yl)-pyridin-3-yl] the solution 1M BH of-4-trifluoromethoxy-benzsulfamide (130mg, 0.30mmol) in THF (15ml) 3.THF (3ml) processes.Crude product is passed through to flash column chromatography purifying (CH 2cl 2: methyl alcohol, 95:5), obtained this title compound (75mg, 60%), be light yellow oil.
MS(ESI+)m/z＝416.1[M+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)0.96(t，J＝7.4Hz，3H)，1.57(m，2H)，2.88(t，J＝7.7Hz，2H)，3.76(t，J＝8.1Hz，2H)，3.98(m，1H)，4.19(t，J＝8.3Hz，2H)，7.04(d，J＝8.4Hz，1H)，7.24(d，J＝8.4Hz，2H)，7.33(bs，1H)，7.50(dd，J＝8.3，2.5Hz，1H)，7.90(d，J＝8.8Hz，2H)，8.33(d，J＝2.3Hz，1H)。
Embodiment 48
4-sec.-propyl-N-[4-(1-propyl group-azetidine-3-yl)-phenyl]-benzsulfamide
48.1 3-(4-nitro-phenyl)-azetidine-1-t-butyl formate
According to the same method of describing in 46.3, use the iodo-azetidine-1-of 3-t-butyl formate (1.74g, 6.14mmol), Zn powder (520mg, 7.95mmol), 1,2-ethylene dichloride (84 μ l, 0.97mmol) and trimethylsilyl chloride (115 μ l, 0.92mmol) make organic zinc compound.Then use Pd 2(dba) 3(90mg, 0.10mmol) and P (2-furyl) 3(85mg, 0.36mmol) is by itself and the bromo-4-oil of mirbane of 1-(1.24g, 6.13mmol) coupling.By crude product by flash column chromatography purifying (heptane: ethyl acetate, 4:1), obtained this title compound (880mg, 52%), be light yellow oil.
MS(ESI+)m/z＝223.1[M-tBu+H] +.
48.2 1-[3-(4-nitro-phenyl)-azetidine-1-yl]-propyl-1-ketone
With the same method of describing in 46.4, by 3-(4-nitro-phenyl)-azetidine-1-formic acid for tertiary butyl ester TFA (15ml) at CH 2cl 2(100ml) mixture in is sloughed protection, and by gained propionyl chloride (290 μ l, 3.31mmol) and triethylamine (470 μ l, 3.37mmol) mixture process in THF (80ml) for amine.By crude product by flash column chromatography purifying (heptane: ethyl acetate, 1:1), obtained this title compound (570mg, 87% liang of step), be brown oil.
MS(ESI+)m/z＝235.1[M+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)1.17(t，J＝7.5Hz，3H)，2.17(q，J＝7.5Hz，2H)，3.93(m，1H)，4.09(dd，J＝9.8，5.9Hz，1H)，4.14(dd，J＝8.3，6.0Hz，1H)，4.47(t，J＝9.3Hz，1H)，4.59(t，J＝8.6Hz，1H)，7.49(d，J＝8.7Hz，2H)，8.24(d，J＝8.7Hz，2H)。
48.3 4-sec.-propyl-N-[4-(1-propionyl-azetidine-3-yl)-phenyl]-benzsulfamide
According to, the same method described in 46.5, by 1-[3-(4-nitro-phenyl)-azetidine-1-yl] the mixture SnCl of-propyl-1-ketone (480mg, 2.04mmol) in EtOH (20ml) 2.2H 2o (2.25g, 9.97mmol) processes, then by half of gained aniline at CH 2cl 2(15ml) pyridine for mixture in (140 μ l, 1.71mmol) and 4-isopropyl benzene SULPHURYL CHLORIDE (230 μ l, 1.28mmol) are processed.By crude product by flash column chromatography purifying (heptane: ethyl acetate, 1:1), obtained this title compound (140mg, 36% liang of step), be faint yellow gum.
MS(ESI+)m/z＝387.1[M+H] +
48.4 4-sec.-propyl-N-[4-(1-propyl group-azetidine-3-yl)-phenyl]-benzsulfamide
According to the same method of describing in embodiment 46.6, by 4-sec.-propyl-N-[4-(1-propionyl-azetidine-3-yl)-phenyl] the mixture 1M BH of-benzsulfamide (140mg, 0.36mmol) in THF (18ml) 3.THF (3.6ml) processes.Rough material being carried out to chromatography purification (ethyl acetate), obtained this title compound (90mg, 67%), is faint yellow oily matter.
MS(ESI+)m/z＝373.1[M+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)δ0.93(t，J＝7.4Hz，3H)，1.24(d， J＝6.9Hz，6H)，1.38(m，2H)，2.41(t，J＝7.5Hz，2H)，2.94(m，1H)，3.03(m，2H)，3.67(m，3H)，7.01(d，J＝8.4Hz，2H)，7.16(d，J＝8.4Hz，2H)，7.28(d，J＝8.5Hz，2H)，7.68(d，J＝8.4Hz，2H)。
Embodiment 49
N-[4-(1-propyl group-azetidine-3-yl)-phenyl]-4-trifluoro-metoxybenzene sulfamide
49.1 N-[4-(1-propionyl-azetidine-3-yl)-phenyl]-4-trifluoromethoxy-benzsulfamide
According to above-described same method, by second half of gained aniline in 48.3 with pyridine (140 μ l, 1.71mmol) and 4-(trifluoromethoxy) benzene sulfonyl chloride (215 μ l, 1.26mmol) at CH 2cl 2(15ml) mixture process in.By crude product by flash column chromatography purifying (heptane: ethyl acetate, 2:1), obtained this title compound (170mg, 40% liang of step), be light yellow gum.
MS(ESI+)m/z＝429.0[M+H] +
49.3 N-[4-(1-propyl group-azetidine-3-yl)-phenyl]-4-trifluoro-metoxybenzene sulfamide
The same method of describing according to embodiment 47.2, by N-[4-(1-propionyl-azetidine-3-yl)-phenyl] the mixture 1M BH of-4-trifluoromethoxy-benzsulfamide (170mg, 0.39mmol) in THF (20ml) 3.THF (3.9ml) processes.This rough material being carried out to chromatography purification (ethyl acetate), obtained this title compound (86mg, 52%), is light yellow oil.
MS(ESI+)m/z＝415.1IM+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)0.90(t，J＝7.4Hz，3H)，1.38(m，2H)，2.43(t，J＝7.5Hz，2H)，3.05(m，2H)，3.68(m，3H)，7.01(d，J＝8.4Hz，2H)，7.18(d，J＝8.4Hz，2H)，7.25(d，J＝8.5Hz，2H)，7.79(d，J＝8.8Hz，2H)。
Embodiment 50
The bromo-N-[2-of 4-(1-propyl group-pyrrolidin-3-yl)-pyrimidine-5-yl]-benzsulfamide.
The bromo-2-vinyl-pyrimidine of 50.1 5-
The 5-iodo-pyrimidine of bromo-2-(9.15g, 32.11mmol) is dissolved in THF (150ml), and adds Pd (PPh 3) 4(18.85g, 1.60mmol), then adds tributyl-vinyl-stannane (9.38ml, 32.11mmol).By gained mixture under microwave irradiation in 140 ℃ heating 20 minutes, then by Celite pad, filter and concentrate.By this roughage CH 2cl 2dilute and wash with water.Layer is separated, and by the dry (Na of organic phase 2sO 4), filter and vacuum concentration, obtained roughage, passed through flash column chromatography purifying (CH 2cl 2), obtained this title compound (4.05g, 68%), be volatility yellow oil, in 4 ℃ can crystallization.
1H NMR(400MHz，CDCl 3)：δ(ppm)5.77(dd，J＝10.5，1.4Hz，1H)，6.62(dd，J＝17.3，1.4Hz，1H)，6.83(dd，J＝17.3，10.5Hz，1H)。
The bromo-2-of 50.2 5-(1-propyl group-pyrrolidin-3-yl)-pyrimidine
With 20 minutes by methoxymethyl-propyl group-trimethyl silyl methyl-amine (14.13g, 74.61mmol) at CH 2cl 2(4ml) solution in is added drop-wise to the bromo-2-vinyl-pyrimidine of 5-(2g, 10.80mmol) and TFA (210 μ l, 2.72mmol) at CH 2cl 2(45ml) in 0 ℃ of cooling solution in.By this reaction mixture in stirring at room 2 hours.By this crude product CH 2cl 2dilution, uses saturated NaHCO 3solution washing, and by organic layer Na 2sO 4be dried and evaporate.Resistates is carried out to silica gel chromatography purifying (CH 2cl 2: methyl alcohol, 97:3), obtained this title compound (1.03g, 34%), be brown oil.
MS(ESI+)m/z＝271.9[M+H] +
50.3 2-(1-propyl group-pyrrolidin-3-yl)-pyrimidine-5-base amine
To be dried flask loads with the bromo-2-of 5-(1-propyl group-pyrrolidin-3-yl)-pyrimidine (300mg, 1.11mmol), Pd 2(dba) 3(three (dibenzalacetone) two palladium (30mg, 0.032mmol)), rac-BINAP (2,2 '-bis-(diphenylphosphino)-1,1 '-dinaphthalene) (35mg, 0.056mmol), tBuONa (150mg, 1.56mmol), benzophenone imine (300mg, 1.65mmol) and toluene (4ml).Then be evacuated, with nitrogen purging, and this mixture heated 3 hours in 80 ℃ under microwave irradiation.After filtering by Celite pad, under vacuum, remove desolventizing.Then roughage is dissolved in THF (10ml), and adds 1N HCl (3ml) aqueous solution.This solution, in stirring at room 45 minutes, is then removed to organic solvent under vacuum.Gained organic phase is adjusted to pH～9 with 2N NaOH solution, uses heptane: ethyl acetate, 2:1 (50ml) washs and concentrates, and has obtained rough amine.
MS(ESI+)m/z＝207.1[M+H] +
The bromo-N-[2-of 50.4 4-(1-propyl group-pyrrolidin-3-yl)-pyrimidine-5-yl]-benzsulfamide
Rough 2-(1-propyl group-pyrrolidin-3-yl)-pyrimidine-5-base amine (about 1.11mmol) is dissolved in to CH 2cl 2: in pyridine 9:1 (50ml), add 4-bromobenzene sulfonyl chloride (566mg, 2.21mmol).After stirred overnight at room temperature, this reaction mixture is filtered and concentrated.Then roughage is dissolved in the solution of EtONa (400mg, 5.87mmol) in EtOH (35ml), and gained solution is heated 1 hour under refluxing.Add silica gel (1g), and removal of solvent under reduced pressure.(CH after column chromatography purifying 2cl 2: methyl alcohol, 9:1), obtained this title compound (100mg, 21% liang of step), be yellow gum.
MS(ESI+)m/z＝426.9[M+H] +
1h NMR (400MHz, CDCl 3): rotational isomer δ (ppm) 0.99 (t, J=7.3Hz, 3H), 1.84 (m, 2H), 2.33 (m, 1H), 2.53 (m, 1H), 3.05 (m, 1H), 3.17 (m, 1H), 3.46 (t, J=6.0Hz, 2H), 3.70 (m, 2H), 3.86 (m, 1H), 5.67 (bs, 1H), 7.53 (d, J=8.4Hz, 2H), 7.70-7.75 (2d, J=8.4Hz, 2H), 8.44 (s, 2H).
Embodiment 51
N-[2-(1-propyl group-pyrrolidin-3-yl)-pyrimidine-5-yl]-4-trifluoromethoxy-benzsulfamide.
According to the same method of describing in embodiment 50.4, use 4-(trifluoromethoxy) benzene sulfonyl chloride (250 μ l, 1.47mmol) at CH the rough 2-obtaining by aforesaid method (1-propyl group-pyrrolidin-3-yl)-pyrimidine-5-base amine (about 0.74mmol) 2cl 2: pyridine, the mixture process in 9:1 (50ml).Then with EtONa/EtOH, process, and crude product is passed through to flash column chromatography purifying (CH 2cl 2: methyl alcohol, 9:1), obtained this title compound (44mg, 14% liang of step), be yellow gum.
MS(ESI+)m/z＝431.0[M+H] +
1h NMR (400MHz, CDCl 3): rotational isomer δ (ppm) 0.98 (t, J=7.3Hz, 3H), 1.84 (m, 2H), 2.30 (m, 1H), 2.58 (m, 1H), 3.14 (m, 2H), 3.31 (m, 1H), 3.64 (m, 2H), 3.92 (m, 2H), 7.24 (m, 2H), 7.93-7.97 (2d, J=8.6Hz, 2H), 8.44 (s, 2H).
Embodiment 52
4-sec.-propyl-N-[2-(1-propyl group-pyrrolidin-3-yl)-pyrimidine-5-yl]-benzsulfamide.
According to the same method of describing in embodiment 50.4, use 4-isopropyl benzene SULPHURYL CHLORIDE (56 μ l, 0.31mmol) at CH the rough 2-obtaining by aforesaid method (1-propyl group-pyrrolidin-3-yl)-pyrimidine-5-base amine (about 0.13mmol) 2cl 2: pyridine, the mixture process in 9:1 (50ml).Then with EtONa/EtOH, process, and crude product is passed through to flash column chromatography purifying (CH 2cl 2: methyl alcohol, 85:15), obtained this title compound (26mg, 50% liang of step), be yellow gum.
MS(ESI+)m/z＝389.1[M+H] +
1h NMR (400MHz, CDCl 3): rotational isomer δ (ppm) 0.96 (t, J=7.4Hz, 3H), 1.21-1.23 (2d, J=6.9Hz, 6H), 1.80 (m, 2H), 2.26 (m, 1H), 2.52 (m, 1H), 2.90 (m, 1H), 3.07 (m, 2H), 3.24 (m, 1H), 3.55 (m, 2H), 3.85 (m, 2H), 6.34 (bs, 1H), 7.25 (m, 2H), 7.76-7.81 (2d, J=8.2Hz, 2H), 8.54 (s, 2H).
Embodiment 53
N-{4-[(S)-1-(3-hydroxyl-propyl)-pyrrolidin-3-yl]-phenyl }-4-sec.-propyl-benzsulfamide 53.1 acetic acid 3-{ (S)-3-[4-(4-sec.-propyl-benzenesulfonyl is amino)-phenyl]-pyrrolidin-1-yl }-propyl diester
0.21g4-sec.-propyl-N-[4-((S)-pyrrolidin-3-yl)-phenyl]-benzsulfamide (0.62mmol) is dissolved in 5ml dimethyl formamide.Add 0.0019mg sodium iodide (0.01mmol) and 0.13ml triethylamine (0.94mmol), then add the bromo-propane of 0.136mg3-acetoxyl group-1-(0.75mmol).In stirring at room 15h, then reaction mixture is poured on 50ml trash ice.Water layer is extracted with ethyl acetate 3 times, and by the organic phase water merging and saturated nacl aqueous solution washing.Ethyl acetate is used to dried over mgso mutually, filter, and reduction vaporization is to dry, has obtained 0.26g raw product.
ESI-MS：445.1[M+H] +
53.2 N-{4-[(S)-1-(3-hydroxyl-propyl)-pyrrolidin-3-yl]-phenyl }-4-sec.-propyl-benzsulfamide
0.26g acetic acid 3-{ (S)-3-[4-(4-sec.-propyl-benzenesulfonyl amino)-phenyl]-pyrrolidin-1-yl }-propyl diester (0.58mmol) is dissolved in 4ml tetrahydrofuran (THF).Add the 0.021g lithium hydroxide (0.88mmol) being dissolved in 4ml water, and by this reaction mixture in stirring at room 15 hours.Add the lithium hydroxide of other equivalent and stir 24h, then by this reaction dilute with water, and being extracted with ethyl acetate 3 times.By the organic phase dried over mgso merging, filter, and reduction vaporization is to dry, has obtained 0.157g product.
ESI-MS：403.3[M+H] +
1h-NMR (CDCl 3): δ [ppm] 7.7 (d, 2H), 7.25 (m, 2H), 7.1 (d, 2H), 6.95 (d, 2H), 3.8 (m, 2H), 3.3 (m, 1H), 3.05 (m, 1H), 2.95 (m, 1H), 2.7-2.9 (m, 4H), 2.55 (m, 1H), 2.25 (m, 1H), 1.7-1.85 (m, 2H), and 1.15-1.3 (wide, 7H).
Embodiment 54
4-cyclobutyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
This title compound is prepared with being similar to the described method of embodiment 37.
ESI-MS：399.1[M+H] +
Embodiment 55
4-oxazole-5-base-N-[4-(1-propyl group-azetidine-3-yl)-phenyl]-benzsulfamide
55.1 4-(1-propyl group-azetidine-3-yl)-phenyl amine
1-(3-(4-nitrophenyl) azetidine-1-yl) third-1-ketone (3.16g, 13.49mmol) is dissolved in ethanol (200ml), and adds SnCl 22H 2o (15.20g, 67.45mmol).By gained mixture backflow 8h, then under vacuum, remove desolventizing.This roughage is dissolved in ethyl acetate, and in succession uses 2N NaOH (x2) aqueous solution and water washing.By the dry (Na of organic layer 2sO 4), by Celite pad, filter and evaporate.Then rough 1-[3-(4-amino-phenyl)-azetidine-1-yl]-propyl-1-ketone be dissolved in tetrahydrofuran (THF) (THF) (200ml) in, and drip 1M LiAlH in 0 ℃ 4mixture in tetrahydrofuran (THF) (19.5ml, 19.5mmol).After stirring at room 2h, in 0 ℃, this reaction mixture is used to THF/H modestly 2o 9:1 (20ml) ends, and then by Celite pad, filter, and the solvent was evaporated under reduced pressure.By this rough 4-(1-propyl group-azetidine-3-yl)-phenyl amine not in addition purifying for next step.
MS(ESI+)m/z＝191.1[M+H] +
55.2 4-oxazole-5-base-N-[4-(1-propyl group-azetidine-3-yl)-phenyl]-benzsulfamide
Rough 4-(1-propyl group-azetidine-3-yl)-phenyl amine (40mg, 0.21mmol) is dissolved in to CH 2cl 2in/pyridine 9:1 (10ml), and add 4-oxazole-5-base-benzene sulfonyl chloride (51mg, 0.21mmol).After stirring at room 2h, by this reaction mixture CH 2cl 2dilution, and in succession use the 1N HCl aqueous solution, saturated NaHCO 3the aqueous solution and water washing.By organic layer Na 2sO 4be dried and concentrate.Resistates is carried out to silica gel chromatography purifying (CH 2cl 2: methyl alcohol, 95:5), obtained this title compound (30mg, 36%), be white amorphous solid.
MS(ESI+)m/z＝398.1[M+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)1.02(t，J＝7.4Hz，3H)，1.75(m，2H)，3.08(m，2H)，3.72(m，2H)，4.24(m，1H)，4.62(m，2H)，7.10(m，2H)，7.22(d，J＝7.9Hz，2H)，7.45(s，1H)，7.69(d，J＝8.4Hz，2H)，7.89(d，J＝8.3Hz，2H)，7.95(s，1H)。
Embodiment 56
4-(the fluoro-ethyl of 2-)-N-[4-(1-propyl group-azetidine-3-yl)-phenyl]-benzsulfamide
According to the same method of describing in embodiment 55, by 4-(1-propyl group-azetidine-3-yl)-phenyl amine (100mg, 0.52mmol) at CH 2cl 24-for mixture in/pyridine 9:1 (12ml) (the fluoro-ethyl of 2-)-benzene sulfonyl chloride (117mg, 0.52mmol) is processed.Crude product is passed through to reverse phase silica gel chromatography purification (H 2o+0.1% acetic acid: CH 3cN+0.1% acetic acid, 75:25), has obtained this title compound (11mg, 6%), is colourless gum.
MS(ESI+)m/z＝377.1[M+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)0.97(t，J＝7.4Hz，3H)，1.59(m，2H)，2.89(m，2H)，3.00(t，J＝6.0Hz，1H)，3.06(t，J＝6.0Hz，1H)，3.76(m，2H)，4.05(m，1H)，4.29(m，2H)，4.57(t，J＝6.0Hz，1H)，4.69(t，J＝6.0Hz，1H)，7.08(d，J＝8.5Hz，2H)，7.12(d，J＝8.5Hz，2H)，7.32(d，J＝8.2Hz，2H)，7.71(d，J＝8.2Hz，2H)。
Embodiment 57
4-(the fluoro-propyl group of 3-)-N-[4-(1-propyl group-azetidine-3-yl)-phenyl]-benzsulfamide
According to the same method of describing in embodiment 55, by 4-(1-propyl group-azetidine-3-yl)-phenyl amine (100mg, 0.52mmol) at CH 2cl 24-for mixture in/pyridine 1:1 (12ml) (the fluoro-propyl group of 3-)-benzene sulfonyl chloride (161mg, 0.68mmol) is processed.Crude product is passed through to reverse phase silica gel chromatography purification (H 2o+0.1% acetic acid: CH 3cN+0.1% acetic acid, 75:25), has obtained this title compound (40mg, 20%), is colourless gum.
MS(ESI+)m/z＝391.3[M+H] +
UH NMR(400MHz，CDCl 3)：δ(ppm)0.96(t，J＝7.4Hz，3H)，1.66(m，2H)，1.97(m，2H)，2.76(m，2H)，3.08(m，1H)，3.25(m，1H)，3.73(m，2H)，4.21(m，1H)，4.34(t，J＝5.7Hz，1H)，4.46(t，J＝5.7Hz，1H)，4.66(m，2H)，7.04(d，J＝8.3Hz，2H)，7.12(d，J＝8.3Hz，2H)，7.25(d，J＝8.1Hz，2H)，7.70(d，J＝8.3Hz，2H)，8.17(s，1H)。
Embodiment 58
The bromo-N-[4-of 4-(1-propyl group-azetidine-3-yl)-phenyl]-benzsulfamide
According to the same method of describing in embodiment 55, by 4-(1-propyl group-azetidine-3-yl)-phenyl amine (1g, 5.25mmol) at CH 2cl 2mixture in/pyridine 9:1 (50ml) is processed with the bromo-benzene sulfonyl chloride of 4-(1.34g, 5.25mmol).Crude product is passed through to flash column chromatography purifying (CH 2cl 2: methyl alcohol, 95:5), obtained this title compound (1.1g, 51%), be colourless gum.
MS(ESI+)m/z＝410.0[M+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)0.92(t，J＝7.4Hz，3H)，1.47(m，2H)，2.60(m，2H)，3.28(m，2H)，3.78(m，1H)，3.91(m，2H)，6.07(bs，1H)，7.07(d，J＝8.4Hz，2H)，7.13(d，J＝8.4Hz，2H)，7.53(d，J＝8.5Hz，2H)，7.64(d，J＝8.5Hz，2H)。
embodiment 59
4-(the fluoro-1-methyl-ethyl of (R)-2-)-N-[4-(1-propyl group-azetidine-3-yl)-phenyl]-benzsulfamide
According to the same method of describing in embodiment 55, by 4-(1-propyl group-azetidine-3-yl)-phenyl amine (150mg, 0.78mmol) at CH 2cl 24-for mixture in/pyridine 1:1 (12ml) (the fluoro-1-methyl-ethyl of (R)-2-)-benzene sulfonyl chloride (242mg, 1.02mmol) is processed.Crude product is passed through to reverse phase silica gel chromatography purification (H 2o+0.1% acetic acid: CH 3cN+0.1% acetic acid, 75:25) has obtained this title compound (15mg, 5%), is colourless gum.
MS(ESI+)m/z＝391.1[M+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)0.93(t，J＝7.3Hz，3H)，1.27(m，3H)，1.60(m，2H)，2.99(m，2H)，3.13(m，1H)，3.86(m，2H)，4.10(m，1H)，4.42(m，5H)，4.36(m，1H)，4.49(m，1H)，7.07(m，4H)，7.27(d，J＝8.3Hz，2H)，7.74(d，J＝8.3Hz，2H)。
Embodiment 60
4-(the fluoro-1-methyl-ethyl of (S)-2-)-N-[4-(1-propyl group-azetidine-3-yl)-phenyl]-benzsulfamide
According to the same method of describing in embodiment 55, by 4-(1-propyl group-azetidine-3-yl)-phenyl amine (110mg, 0.57mmol) at CH 2cl 24-for mixture in/pyridine 1:1 (12ml) (the fluoro-1-methyl-ethyl of (S)-2-)-benzene sulfonyl chloride (178mg, 0.75mmol) is processed.Crude product is passed through to flash column chromatography purifying (CH 2cl 2: methyl alcohol, 95:5), obtained this title compound (50mg, 22%), be gum.
MS(ESI+)m/z＝391.1[M+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)0.93(t，J＝7.3Hz，3H)，1.27(m，3H)，1.60(m，2H)，2.92(m，2H)，3.15(m，1H)，3.73(m，2H)，4.06(m，1H)，4.32(m，2H)，4.36(m，1H)，4.49(m，1H)，7.07(m，4H)，7.28(d，J＝8.3Hz，2H)，7.74(d，J＝8.3Hz，2H)。
Embodiment 61
N-[4-(1-propyl group-azetidine-3-yl)-phenyl]-4-(the fluoro-propyl group of 3,3,3-tri-)-benzsulfamide
According to the same method of describing in embodiment 55, by 4-(1-propyl group-azetidine-3-yl)-phenyl amine (100mg, 0.52mmol) at CH 2cl 24-for mixture in/pyridine 9:1 (12ml) (the fluoro-propyl group of 3,3,3-tri-)-benzene sulfonyl chloride (214mg, 0.78mmol) is processed.Crude product is passed through to flash column chromatography purifying (CH 2cl 2: methyl alcohol, 95:5), has obtained this title compound (26mg, 11%), colourless gum.
MS(ESI+)m/z＝427.1[M+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)0.99(t，J＝7.4Hz，3H)，1.73(m，2H)，2.36(m，2H)，2.87(m，2H)，3.10(m，2H)，3.70-4.20(m，5H)，7.15(m，4H)，7.24(d，J＝8.5Hz，2H)，7.79(d，J＝8.3Hz，2H)。
Embodiment 62
N-[4-(1-propyl group-azetidine-3-yl)-phenyl]-4-(the fluoro-ethyl of 2,2,2-tri-)-benzsulfamide
According to the same method of describing in embodiment 55, by 4-(1-propyl group-azetidine-3-yl)-phenyl amine (100mg, 0.52mmol) at CH 2cl 24-for mixture in/pyridine 9:1 (10ml) (the fluoro-ethyl of 3,3,3-tri-)-benzene sulfonyl chloride (163mg, 0.63mmol) is processed.Crude product is passed through to flash column chromatography purifying (CH 2cl 2: methyl alcohol, 95:5), obtained this title compound (65mg, 30%), be colourless gum.
MS(ESI+)m/z＝413.1[M+H] +
1H NMR(400MHz，CDCl 3)：δ(ppm)0.98(t，J＝7.4Hz，3H)，1.71(m，2H)，3.09(m，2H)，3.38(m，2H)，3.66-4.75(m，5H)，7.13(m，4H)，7.33(d，J＝8.0Hz，2H)，7.83(d，J＝8.1Hz，2H)。
Embodiment 63
N-[4-(1-propyl group-azetidine-3-yl)-phenyl]-4-(the fluoro-1-methyl-ethyl of 2,2,2-tri-)-benzsulfamide
According to the same method of describing in embodiment 55, by 4-(1-propyl group-azetidine-3-yl)-phenyl amine (100mg, 0.52mmol) at CH 2cl 24-for mixture in/pyridine 9:1 (15ml) (the fluoro-1-methyl-ethyl of 2,2,2-tri-)-benzene sulfonyl chloride (145mg, 0.52mmol) is processed.Crude product is passed through to flash column chromatography purifying (CH 2cl 2: methyl alcohol, 95:5), obtained this title compound (40mg, 18%), be light yellow gum.
MS(ESI+)m/z＝427.1[M+H] +
1H-NMR(400MHz，CDCl 3)：δ(ppm)0.98(t，J＝7.4Hz，3H)，1.49(d，J＝7.2Hz，3H)，1.68(m，2H)，3.02-3.21(m，2H)，3.47(m，1H)，3.68-4.70(m，5H)，7.07(d，J＝8.6Hz，2H)，7.12(d，J＝8.5Hz，2H)，7.40(d，J＝8.2Hz，2H)，7.76(d，J＝8.3Hz，2H)。
Embodiment 64
4-(the fluoro-1-methyl-ethyl of 2,2-bis-)-N-[4-(1-propyl group-azetidine-3-yl)-phenyl]-benzsulfamide;
According to the same method of describing in embodiment 55, by 4-(1-propyl group-azetidine-3-yl)-phenyl amine (150mg, 0.78mmol) at CH 2cl 24-for/pyridine 1:1 (12ml) (the fluoro-1-methyl-ethyl of 2,2-bis-)-benzene sulfonyl chloride (321mg, 1.26mmol) is processed.Crude product is passed through to flash column chromatography purifying (CH 2cl 2: methyl alcohol, 95:5), obtained this title compound (40mg, 18%), be colourless gum.
MS(ESI+)m/z＝409.1[M+H] +
1H-NMR(400MHz，CDCl 3)：δ(ppm)0.97(t，J＝7.4Hz，3H)，1.36(m，3H)，1.69(m，2H)，3.07(m，2H)，3.17(m，1H)，3.54-4.65(m，5H)，5.76(td，J＝3.5Hz，1H)，7.11(m，4H)，7.30(d，J＝8.1Hz，2H)，7.78(d，J＝8.3Hz，2H)。
Embodiment 65
N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-4-[1,2,3] thiadiazoles-4-base-benzsulfamide
Sulphonamide coupling is to realize according to being similar to the method for describing in embodiment 55.Output: 75mg (52%).
MS(ESI)m/z：429.0[M+H] +
1H-NMR(DMSO-d 6)：δ[ppm]9.75(s，1H)，8.29(d，2H)，7.91(d，2H)，7.13(d，2H)，7.04(d，1H)，3.16(m，1H)，2.83(m，1H)，2.60(t，1H，J＝7.3Hz，2H)，2.23(m，3H)，2.15(m，1H)，1.65(m，1H)，1.43(m，2H)，0.85(t，J＝7.3Hz，3H)。
Embodiment 66
N-[2-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-4-[1,2,3] thiadiazoles-4-base-benzsulfamide
Sulphonamide coupling is to realize according to being similar to the method for describing in embodiment 55.Output:: 15mg (10%)
MS(ESI)m/z：429.0[M+H] +
1H-NMR(DMSO-d 6)：δ[ppm]9.73(s，1H)，8.30(d，2H)，7.88(d，2H)，7.12(t，1H)，6.98(m，3H)，3.16(m，1H)，2.81(m，1H)，2.60(t，1H，J＝7.3Hz，2H)，2.23(m，3H)，2.14(m，1H)，1.58(m，1H)，1.39(m，2H)，0.82(t，J＝7.3Hz，3H)。
Embodiment 67
N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-4-pyrrolidin-1-yl-benzsulfamide
The bromo-N[4-of 4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl obtaining in embodiment 25] benzsulfamide starts, and according to embodiment 50 similar method (tetramethyleneimine, BINAP, tert-NaOC 4h 9, Pd 2(dba) 3, 140 ℃ of MW (microwave)), obtain this title compound.Chromatography CH 2cl 2-methyl alcohol 9:1.
Productive rate: 36mg (14%).
MS(ESI)m/z：414.1[M+H] +
1H-NMR(DMSO-d 6)：δ[ppm]9.85(brs，1H)，7.50(d，2H)，7.11(d，2H)，7.00(d，2H)，6.51(d，2H)，3.30(m，6H)，2.91(m，2H)，2.63(m，3H)，2.19(m，1H)，1.87(m，4H)，1.73(m，1H)，1.51(m，2H)，0.85(t，J＝7.3Hz，3H)。
Embodiment 68
N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-4-trifluoromethylthio-benzsulfamide
In-78 ℃, 4-((S)-1-propyl pyrrole alkane-3-yl) phenyl amine (50mg, 0.24mmol) is dissolved in THF (5ml), and adds hexamethyldisilazane potassium (146mg, 0.73mmol).This is reacted on to-78 ℃ and stir 1 hour, then add 4-(trifluoromethylthio) benzene-1-fluorosulfonyl (64mg, 0.24mmol), and this solution is risen to ambient temperature overnight.Solvent removed in vacuo, and resistates is distributed between ethyl acetate and NaOH (2M).Organic extract is separated, dry (MgSO 4), filter and concentrate, obtained product (97mg, productive rate 89%).
MS(ESI)m/z：445.0[M+H] +
1H-NMR(DMSO-d 6)：δ[ppm]10.27(brs，1H)，7.87(m，2H)，7.68(m，2H)，7.19(d，2H)，7.03(d，2H)，3.30(m，2H)，3.16(m，2H)，2.82(m，3H)，2.26(m，1H)，1.82(m，1H)，1.53(m，2H)，0.88(t，J＝7.3Hz，3H)。
Embodiment 69
N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-4-pyrazol-1-yl-benzsulfamide
Sulphonamide coupling is to realize according to being similar to the method for describing in embodiment 55.2; Obtained this title compound of 2mg (34%).
MS(ESI)m/z：411.1[M+H] +
1H-NMR(CH 3OH-d 4)：δ[ppm]8.30(s，1H)，7.84(m，4H)，7.72(s，1H)，7.19(d，2H)，7.08(d，2H)，6.52(s，1H)，3.50(m，2H)，3.30(m，2H)， 2.96(m，2H)，2.38(m，1H)，2.02(m，1H)，1.68(m，2H)，0.96(t，J＝7.3Hz，3H)。
Embodiment 70
4-oxazole-5-base-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
Sulphonamide coupling is to realize according to being similar to the method for describing in embodiment 55.2.Obtained this title compound of 148mg (productive rate 84%).
MS(ESI)m/z：412.1[M+H] +
1H-NMR(CH 3OH-d 4)：δ[ppm]8.28(s，1H)，7.79(m，4H)，7.62(s，1H)，7.20(d，2H)，7.13(d，2H)，3.69(m，1H)，3.53(m，1H)，3.47(m，2H)，3.12(m，3H)，2.38(m，1H)，2.10(m，1H)，1.75(m，2H)，0.99(t，J＝7.3Hz，3H)。
Embodiment 71
4-oxazole-5-base-N-[2-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
Sulphonamide coupling is to realize according to being similar to the method for describing in embodiment 55.2.Obtained this title compound of 11mg (productive rate 6%).
MS(ESI)m/z：412.1[M+H] +
1H-NMR(CH 3OH-d 4)：δ[ppm]8.29(s，1H)，7.82(m，4H)，7.66(s，1H)，7.21(m，1H)，7.06(m，3H)，3.61(m，1H)，3.50(m，1H)，3.37(m，2H)，3.03(m，3H)，2.38(m，1H)，2.05(m，1H)，1.69(m，2H)，0.99(t，J＝7.3Hz，3H)。
Embodiment 72
4-(2-oxo-pyrrolidin-1-yl)-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
Sulphonamide coupling is to realize according to being similar to the method for describing in embodiment 55.2.Obtained this title compound of 86mg (productive rate 66%).
MS(ESI)m/z：428.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]7.72(m，4H)，7.12(d，2H)，7.01(d，2H)，3.83(t，2H)，3.32(m，1H)，3.14(m，1H)，2.92(m，1H)，2.81(m，1H)，2.53(m，5H)，2.27(m，1H)，2.13(m，2H)，1.83(m，1H)，1.52(m，2H)，0.91(t，J＝7.3Hz，3H)。
Embodiment 73
4-furans-2-base-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
The bromo-N[4-of 4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl obtaining in embodiment 25] benzsulfamide starts, and according to the method that is similar to embodiment 19, obtained this title compound 92mg (productive rate 76%)).
MS(ESI)m/z：412.1[M+H] +
1H-NMR(CH 3OH-d 4)：δ[ppm]7.73(s，4H)，7.61(s，1H)，7.19(d，2H)，7.12(d，2H)，6.91(s，1H)，6.52(s，1H)，3.95-3.40(m，5H)，3.32(m，1H)，3.20(m，2H)，2.15(m，1H)，1.74(m，2H)，0.99(t，J＝7.3Hz，3H)。
Embodiment 74
N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-4-pyrroles-1-base-benzsulfamide
Sulphonamide coupling is to realize according to being similar to the method for describing in embodiment 55.Obtained this title compound of 86mg (productive rate 66%).
MS(ESI)m/z：411.1[M+H] +
1H-NMR(CH 3OH-d 4)：δ[ppm]7.78(d，2H)，7.76(s，1H)，7.61(d，2H)，7.26(s，1H)，7.18(d，2H)，7.09(d，2H)，6.31(s，1H)，3.36(m，2H)，3.17(m，1H)，3.08(m，1H)，2.82(m，3H)，2.32(m，1H)，1.95(m，1H)，1.62(m，2H)，0.97(t，J＝7.4Hz，3H)。
Embodiment 75
4-azetidine-1-base-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
This title compound is to prepare with being similar to the method for describing in embodiment 67.Obtained this title compound of 9mg (productive rate 11%).
MS(ESI)m/z：400.2[M+H] +
1H-NMR(CH 3OH-d 4)：δ[ppm]7.50(d，2H)，7.12(d，2H)，7.03(d，2H)，6.31(d，2H)，3.89(m，4H)，3.49(m，2H)，3.26(m，2H)，2.92(m，3H)，2.33(m，3H)，2.02(m，1H)，1.68(m，2H)，0.97(t，J＝7.3Hz，3H)。
Embodiment 76
4-(2-oxo-oxazolidines-3-yl)-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
This title compound is to prepare with being similar to the method for describing in embodiment 67.Obtained this title compound of 7mg (productive rate 10%).
MS(ESI)m/z：430.2[M+H] +
1H-NMR(CDCl 3)：δ[ppm]7.74(d，2H)，7.68(d，2H)，7.14(d，2H)，7.07(d，2H)，4.50(m，2H)，4.10(m，2H)，3.50(m，4H)，2.96(m，3H)，2.37(m，1H)，2.01(m，1H)，1.68(m，2H)，0.98(t，J＝7.3Hz，3H)。
Embodiment 77
4-(the fluoro-1-methyl-ethyl of 2,2-bis-)-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
Sulphonamide coupling is to realize according to being similar to the method for describing in embodiment 55.2.By chromatography purification, use ethyl acetate-CH 2cl 21:1 wash-out, obtains this title compound of 36mg (productive rate 12%).
MS(ESI)m/z：423.1[M+H] +
1H-NMR(CDCl 3)：δ[ppm]7.74(d，2H)，7.52(d，2H)，7.14(d，2H)，7.03(d，2H)，6.14(m，1H)，3.30(m，5H)，2.82(m，1H)，2.65(t，1H，J＝7.3Hz，2H)，2.39(m，2H)，2.15(m，1H)，1.65(m，1H)，1.41(m，1H)，1.31(d，3H)，0.98(t，J＝7.3Hz，3H)。
Embodiment 78
N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-4-(the fluoro-1-methyl-ethyl of 2,2,2-tri-)-benzsulfamide
Sulphonamide coupling is to realize according to being similar to the method for describing in embodiment 55.2.Obtained this title compound of 57mg (productive rate 43%).
MS(ESI)m/z：441.1[M+H] +
1H-NMR(CH 3OH-d 4)：δ[ppm]7.72(d，2H)，7.49(d，2H)，7.12(d，2H)，7.03(d，2H)，
3.65(m，2H)，3.24(m，1H)，3.10(m，1H)，2.90(m，1H)，2.70(m，1H)，2.51(m，3H)，2.25(m，1H)，1.82(m，1H)，1.57(m，2H)，1.47(d，3H)，0.94(t，J＝7.3Hz，3H)。
Embodiment 79
Cumarone-2-sulfonic acid [4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-acid amides
Sulphonamide coupling is to realize according to being similar to the method for describing in embodiment 55.2.By chromatography purification (using ethyl acetate-methyl alcohol 1-50% wash-out), obtain this title compound of 52mg (productive rate 24%).
MS(ESI)m/z：385.1[M+H] +
1H-NMR(DMSO-d 6)：δ[ppm]10.50(brs，1H)，7.76(d，1H)，7.70(d，1H)，7.55(m，3H)，7.34(m，1H)，7.18(d，2H)，7.10(d，2H)，3.10(m，1H)，2.90(m，1H)，2.61(m，5H)，2.22(m，1H)，1.76(m，1H)，1.52(m，3H)，0.86(t，J＝7.3Hz，3H)。
Embodiment 80
5-isoxazole-5-base-thiophene-2-sulfonic acid [4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-acid amides
4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl amine (100mg, 0.49mmol) is dissolved in tetrahydrofuran (THF) (5ml).Subsequently, add dimethyl aminopyridine (24mg, 0.20mmol) and 5-(5-isoxazolyl) thiophene-2-SULPHURYL CHLORIDE (159mg, 0.64mmol), and by this reaction mixture in stirred overnight at room temperature.The solvent was evaporated under reduced pressure, and resistates water and ethyl acetate are processed.By organic layer use dried over mgso, filter, and the solvent was evaporated under reduced pressure, obtained crude product.Crude product, by silica gel chromatography purifying, as eluent, has been obtained to the product (67mg, 33%) of purifying by methylene chloride/methanol (100:0-96:4).
MS(ESI)m/z：418.1[M+H] +
1H-NMR(DMSO-d 6)：δ[ppm]8.65(s，1H)，7.63(d，1H)，7.58(d，1H)，7.24(d，2H)，7.12(m，3H)，7.07(s，1H)，4.02(m，1H)，3.16(d，2H)，3.10(m，3H)，2.28(m，1H)，1.91(m，1H)，1.58(m，2H)，0.88(t，J＝7.3Hz，3H)。
Embodiment 81
5-isoxazole-3-base-thiophene-2-sulfonic acid [4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-acid amides
Sulphonamide coupling is to realize according to being similar to the method for describing in embodiment 80.Amount with 66mg has obtained this title compound; Productive rate 32%.
MS(ESI)m/z：418.1[M+H] +
1H-NMR(DMSO-d 6)：δ[ppm]8.72(s，1H)，7.68(d，1H)，7.62(d，1H)，7.24(d，2H)，7.14(m，3H)，7.09(s，1H)，4.08(m，1H)，3.16(d，2H)，3.10(m，3H)，2.33(m，1H)，1.97(m，1H)，1.62(m，2H)，0.92(t，J＝7.3Hz，3H)。
Embodiment 82
5-oxazole-5-base-thiophene-2-sulfonic acid [4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-acid amides
Sulphonamide coupling is to realize according to being similar to the method for describing in embodiment 80.Amount with 110mg has obtained this title compound; (productive rate 54%).
MS(ESI)m/z：418.1[M+H] +
1H-NMR(CH 3OH-d 4)：δ[ppm]8.70(s，1H)，7.68(d，1H)，7.62(d，1H)，7.36(d，2H)，7.14(m，3H)，7.09(s，1H)，4.05(m，1H)，3.18(d，2H)，3.04(m，3H)，2.32(m，1H)，1.93(m，1H)，1.59(m，2H)，0.91(t，J＝7.3Hz，3H)。
Embodiment 83
N-(4-azetidine-3-base-phenyl)-4-(the fluoro-1-methyl-ethyl of 2,2-bis-)-benzsulfamide
Step 1: according to being similar to the method for using in embodiment 55, use 4-(1,1-difluoro, third-2-yl) benzene-1-SULPHURYL CHLORIDE, carry out sulphonamide coupling.Obtained this title compound of 90mg (29%).
MS(ESI)m/z：467.1[M+H] +
Step 2: carry out boc deprotection according to being similar to the method for using in embodiment 46.4.Obtained this title compound of 77mg (100%).
MS(ESI)m/z：367.1[M+H] +
Embodiment 84
4-sec.-propyl-N-[4-((S)-1-ethyl-pyrrolidin-3-yl)-phenyl]-benzsulfamide
0.3g4-sec.-propyl-N-((S)-4-pyrrolidin-3-yl-phenyl)-benzsulfamide (0.87mmol) is dissolved in 20ml methylene dichloride.Add after 0.07ml acetic acid, 0.073ml acetaldehyde (1.31mmol) and 0.277g sodium triacetoxy borohydride (1.31mmol), by this reaction mixture stirring at room 30 minutes.By solvent evaporation, resistates is dissolved in water, and with aqueous sodium hydroxide solution by pH regulator to pH8-9.By water extracted with diethyl ether three times, by the organic phase dried over mgso merging, filter, and the solvent was evaporated under reduced pressure.Crude product, via silica gel chromatography purifying (chromabond post), as eluent, has been obtained to this title compound of 64mg by methylene dichloride, methylene chloride/methanol 4%.
ESI-MS：373.25[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.7(d，2H)，7.3(d，2H)，7.15(d，2H)，7.0(d，2H)，6.1(bs，1H)，3.35(m，1H)，3.1(m，1H)，2.95(m，2H)， 2.65(m，2H)，2.55(m，1H)，2.45(m，1H)，2.3(m，1H)，1.85(m，1H)，1.25(d，6H)，1.15(t，3H)。
Embodiment 85
4-sec.-propyl-N-[4-((S)-1-methyl-pyrrolidin-3-yl)-phenyl]-benzsulfamide
4-sec.-propyl-N-[4-((S)-1-methyl-pyrrolidin-3-yl)-phenyl]-benzsulfamide is as embodiment 84 preparation of describing, but use formalin as carbonyl reagent source.
ESI-MS：359.2[M+H] +
1h-NMR (CDCl 3, 400MHz): δ [ppm] 7.7 (d, 2H), 7.3 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 6.0 (s, wide, 1H), 3.3 (m, 1H), 3.0 (m, 1H), 2.95 (m, 1H), 2.85 (m, 1H), 2.7 (m, 1H), 2.5 (m, 1H), 2.4 (s, 3H), 2.3 (m, 1H), 1.8 (m, 1H), 1.2 (m, 6H).
According to above-described embodiment, be prepared into 86-93.Described compound characterizes by following physical data.
Embodiment 86
4-(the fluoro-ethyl of 2-)-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide, hydrochloric acid
ESI-MS：391.4[M+H] +
UH-NMR(DMSO-d 6，400MHz)：δ[ppm]11.35(bs，1H)，10.35(m，1H)，7.75(d，2H)，7.45(d，2H)，7.35(m，2H)，7.1(m，2H)，4.7(m，1H)，4.6(m，1H)，3.8-3.2(m，5H)，3.15-2.95(m，4H)，2.3(m，1H)，2.0(m，1H)，1.7(m，2H)，0.9(t，3H)。
Embodiment 87
4-(the fluoro-1-methyl-ethyl of (S)-2-)-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
ESI-MS：405.15[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.75(d，2H)，7.3(d，2H)，7.15(d，2H)，7.0(d，2H)，5.35(bs，1H)，4.5(m，1H)，4.4(m，1H)，3.3(m，1H)，3.15(m，1H)，3.05(m，1H)，2.85(m，1H)，2.65(m，1H)，2.5(m，1H)，2.45(m，2H)，2.3(m，1H)，1.8(m，1H)，1.55(m，2H)，1.3(d，3H)，0.9 (t，3H)。
Embodiment 88
N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-4-(the fluoro-propyl group of 3,3,3-tri-)-benzsulfamide
ESI-MS：441.1[M+H] +
1h-NMR (CDCl 3, 400MHz): δ [ppm] 7.75 (d, 2H), 7.25 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.7 (bs, 1H), 3.3 (m, 1H), 3.05 (m, 1H), 2.9 (m, 3H), 2.7 (m, 1H), 2.2-2.6 (several m, 6H), 1.8 (m, 1H), 1.55 (m, 2H), 0.9 (t, 3H).
Embodiment 89
5-propyl group-thiophene-2-sulfonic acid [4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-acid amides
ESI-MS：393.1[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.3(d，1H)，7.2(d，2H)，7.05(d，2H)，6.65(d，1H)，3.35(m，1H)，3.1(m，1H)，2.9(m，1H)，2.75(m，3H)，2.5(m，3H)，2.3(m，1H)，1.85(m，1H)，1.5-1.7(m，4H)，0.9(m，6H)。
Embodiment 90
N-[4-((R)-1-allyl group-pyrrolidin-3-yl)-phenyl]-4-(the fluoro-cyclopropyl of 2,2-bis-)-benzsulfamide
ESI-MS：419.1[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.65(d，2H)，7.2(d，2H)，7.05(d，2H)，6.95(d，2H)，6.0(bs，1H)，5.8(m，1H)，5.15(d，1H)，5.05(d，1H)，3.25(m，1H)，3.1(m，2H)，2.95(m，1H)，2.8(m，1H)，2.7(m，1H)，2.6(m，1H)，2.4(m，1H)，2.2(m，1H)，1.8(m，1H)，1.7(m，1H)，1.55(m，1H)。
Embodiment 91
5-methyl-pyridine-2-sulfonate [4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-acid amides
ESI-MS：360.1[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]8.5(s，1H)，7.9(bs，1H)，7.8(d，1H)，7.6(d，1H)，7.15(d，2H)，7.1(d，2H)，3.25(m，1H)，3.0(m，1H)，2.85(m，1H)，2.6(m，1H)，2.5(m，1H)，2.4(m，2H)，2.4(s，3H)，2.2(m，1H)，1.75(m，1H)，1.5(m，2H)，0.9(t，3H)。
Embodiment 92
4-(the fluoro-propyl group of 3-)-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
ESI-MS：405.1[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.7(d，2H)，7.25(d，2H)，7.1(d，2H)，7.0(d，2H)，6.3(bs，1H)，4.4(dt，2H)，3.3(m，1H)，3.0(m，1H)，2.85(m，1H)，2.8(m，2H)，2.7(m，1H)，2.55(m，1H)，2.45(m，2H)，2.3(m，1H)，2.0(m，2H)，1.8(m，1H)，1.55(m，2H)，0.9(t，3H)。
Embodiment 93
4-(the fluoro-1-methyl-ethyl of (R)-2-)-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
ESI-MS：405.15[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.75(d，2H)，7.3(d，2H)，7.15(d，2H)，7.0(d，2H)，5.5(bs，1H)，4.5(m，1H)，4.4(m，1H)，3.3(m，1H)，3.15(m，1H)，3.05(m，1H)，2.85(m，1H)，2.65(m，1H)，2.5(m，1H)，2.45(m，2H)，2.3(m，1H)，1.8(m，1H)，1.55(m，2H)，1.3(d，3H)，0.9(t，3H)。
Embodiment 94
N-[4-((S)-1-cyclopropyl methyl-pyrrolidin-3-yl)-phenyl]-4-sec.-propyl-benzsulfamide
N-[4-((S)-1-cyclopropyl methyl-pyrrolidin-3-yl)-phenyl]-4-sec.-propyl-benzsulfamide be as in embodiment 84 for 4-sec.-propyl-N-[4-((S)-1-ethyl-pyrrolidin-3-yl)-phenyl] description of-benzsulfamide prepares, but uses cyclopropyl formaldehyde as carbonyl reagent.
ESI-MS：399.1[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.65(d，2H)，7.25(d，2H)，7.1(d，2H)，6.95(d，2H)，5.25(s，1H)，3.3(m，1H)，3.15(m，1H)，2.9(m，2H)，2.65(m，1H)，2.6(m，1H)，2.4(m，1H)，2.35(m，2H)，2.25(m，1H)，1.75(m，1H)，1.2(d，6H)，0.9(m，1H)，0.45(d，2H)，0.1(d，2H)。
According to above-described embodiment, be prepared into embodiment 95-119.Described compound characterizes by following physical data.
Embodiment 95
4-(the fluoro-1-methyl fluoride-ethyl of 2-)-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
ESI-MS：423.15[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.75(d，2H)，7.35(d，2H)，7.15(d，2H)，7.0(d，2H)，5.3(s，1H)，4.75(d，2H)，4.65(d，2H)，3.3(m，1H)，3.05(m，1H)，2.85(m，2H)，2.65(m，1H)，2.45(m，4H)，2.3(m，1H)，1.8(m，1H)，1.55(m，2H)，0.9(t，3H)。
Embodiment 96
N-{4-[(S)-1-(the fluoro-ethyl of 2-)-pyrrolidin-3-yl]-phenyl }-4-sec.-propyl-benzsulfamide
ESI-MS：391.1[M+H] +
1h-NMR (CDCl 3, 400MHz): δ [ppm] 7.7 (d, 2H), 7.3 (d, 2H), 7.15 (d, 2H), 7.0 (d, 2H), 4.63 (t, 1H), 4.5 (t, 1H), 3.3 (m, 1H), 3.1 (m, 1H), 2.7-3.0 (several m, 5H), 2.5 (m, 1H), 2.25 (m, 1H), 1.8 (m, 1H), 1.2 (d, 6H).
Embodiment 97
4-sec.-propyl-N-[4-((S)-1-propionyl-pyrrolidin-3-yl)-phenyl]-benzsulfamide
ESI-MS：401.15[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.7(d，2H)，7.3(m，3H)，7.1(m，3H)，4.0(m，0.5H)，3.8(m，2H)，3.65(m，0.5H)，3.5(m，1H)，3.35(m，2H)，2.95(sept，1H)，2.8(m，3H)，1.95(m，1H)，1.2(d，6H)，1.15(m，3H)。
Embodiment 98
N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-3-trifluoromethoxy-benzsulfamide
ESI-MS：429.15[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.7(d，1H)，7.55(s，1H)，7.5(t，1H)，7.4(d，1H)，7.15(d，2H)，6.95(d，2H)，5.3(bs，1H)，3.3(m，1H)，3.05(m，1H)，2.85(m，1H)，2.65(m，1H)，2.5(m，1H)，2.45(m，2H)，2.3(m，1H)，1.8(m，1H)，1.55(m，2H)，0.9(t，3H)。
Embodiment 99
N-[2-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-3-trifluoromethoxy-benzsulfamide
ESI-MS：429.15[M+H] +
Embodiment 100
N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-2-trifluoromethyl-benzsulfamide
ESI-MS：413.15[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]8.0(d，1H)，7.85(d，1H)，7.65(t，1H)，7.55(t，1H)，7.1(d，2H)，6.95(d，2H)，5.9(bs，1H)，3.3(m，1H)，3.0(m，1H)，2.8(m，1H)，2.6(m，1H)，2.45(m，1H)，2.4(m，2H)，2.25(m，1H)，1.75(m，1H)，1.55(m，2H)，0.95(t，3H)。
Embodiment 101
N-[4-((S)-1-allyl group-pyrrolidin-3-yl)-phenyl]-4-trifluoromethoxy-benzsulfamide
ESI-MS：427.1[M+H] +
1h-NMR (DMSO-d 6, 400MHz): δ [ppm] 11.3 (bd, 1H), 10.45 (m, 1H), 7.9 (d, 2H), 7.55 (d, 2H), 7.25 (m, 2H), 7.1 (d, 2H), 6.0 (m, 1H), 5.5 (m, 1H), 5.45 (m, 1H), 3.8 (m, 2H), 2.9-3.75 (several m, 5H), 2.3 (m, 1H), 1.95 (m, 1H).
Embodiment 102
N-((S)-4-pyrrolidin-3-yl-phenyl)-4-trifluoromethoxy-benzsulfamide
ESI-MS：387.05[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]7.85(d，2H)，7.45(d，2H)，7.05 (d，2H)，6.95(d，2H)，5.2(m，1H)，3.3(m，1H)，3.1(m，2H)，3.05(m，1H)，2.7(m，1H)，2.15(m，1H)，1.7(m，1H)
Embodiment 103
N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-4-(the fluoro-ethyl of 2,2,2-tri-)-benzsulfamide
ESI-MS：427.2[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.8(d，2H)，7.4(d，2H)，7.15(d，2H)，7.0(d，2H)，5.7(bs，1H)，3.4(m，2H)，3.3(m，1H)，3.05(m，1H)，2.85(m，1H)，2.7(m，1H)，2.5(m，3H)，2.3(m，1H)，1.8(m，1H)，1.55(m，2H)，0.9(t，3H)。
Embodiment 104
N-[4-((S)-1-ethyl-pyrrolidin-3-yl)-phenyl]-4-trifluoromethoxy-benzsulfamide
ESI-MS：415.1[M+H] +
1h-NMR (CDCl 3, 400MHz): δ [ppm] 7.8 (d, 2H), 7.25 (d, 2H), 7.15 (d, 2H), 7.0 (d, 2H), 4.9 (bs, 1H), 3.3 (m, 1H), 3.05 (m, 1H), 2.85 (m, 1H), 2.5-2.7 (several m, 3H), 2.45 (m, 1H), 2.3 (m, 1H), 1.8 (m, 1H), 1.15 (t, 3H).
Embodiment 105
Chloro-thiophene-the 2-of 5-sulfonic acid [4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-acid amides
ESI-MS：385.0[M+H] +
1h-NMR (CDCl 3, 400MHz): δ [ppm] 7.25 (d, 1H), 7.2 (d, 2H), 7.0 (d, 2H), 6.8 (d, 1H), 5.1 (bs, 1H), 3.3 (m, 1H), 3.05 (m, 1H), 2.85 (m, 1H), 2.7 (m, 1H), 2.4-2.6 (several m, 3H), 2.3 (m, 1H), 1.8 (m, 1H), 1.55 (m, 2H), 0.9 (t, 3H).
Embodiment 106
N-[4-((S)-1-allyl group-pyrrolidin-3-yl)-phenyl]-4-(the fluoro-1-methyl-ethyl of (S)-2-)-benzsulfamide
ESI-MS：403.4[M+H] +
Embodiment 107
N-[4-((S)-1-allyl group-pyrrolidin-3-yl)-phenyl]-4-(the fluoro-propyl group of 3-)-benzsulfamide
ESI-MS：403.15[M+H] +
Embodiment 108
4-(the fluoro-propyl group of 3-)-N-((S)-4-pyrrolidin-3-yl-phenyl)-benzsulfamide
ESI-MS：363.1[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]7.7(d，2H)，7.4(d，2H)，7.1(d，2H)，7.0(d，2H)，4.6(bs)，4.5(m，1H)，4.35(m，1H)，3.15(m，1H)，3.0(m，2H)，2.9(m，1H)，2.7(m，2H)，2.6(m，1H)，2.05(m，1H)，1.95(m，1H)，1.9(m，1H)，1.6(m，1H)。
Embodiment 109
4-(the fluoro-1-methyl-ethyl of (S)-2-)-N-((S)-4-pyrrolidin-3-yl-phenyl)-benzsulfamide
ESI-MS：363.05[M+H] +
1h-NMR (CH 3oH-d 4, 400MHz): δ [ppm] 7.7 (d, 2H), 7.4 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 4.5 (m, 1H), 4.4 (m, 1H), 2.95-3.35 (several m, 6H), 2.7 (m, 1H), 2.2 (m, 1H), 1.3 (d, 3H).
Embodiment 110
4-(the fluoro-1-methyl-ethyl of (R)-2-)-N-((S)-4-pyrrolidin-3-yl-phenyl)-benzsulfamide
ESI-MS：363.1[M+H] +
1h-NMR (acetic acid-d 4, 400MHz): δ [ppm] 7.7 (d, 2H), 7.4 (d, 2H), 7.2 (m, 4H), 4.55 (m, 1H), 4.45 (m, 1H), 3.8 (m, 1H), 3.65 (m, 1H), 3.5 (m, 2H), 3.2 (m, 2H), 2.4 (m, 1H), 2.05 (m, 1H), 1.3 (d, 3H).
Embodiment 111
N-[4-((S)-1-methyl-pyrrolidin-3-yl)-phenyl]-4-trifluoromethoxy-benzsulfamide
ESI-MS：401.1[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]7.9(d，2H)，7.55(d，2H)，7.15(d，2H)，7.0(d，2H)，3.2(m，1H)，2.8(m，1H)，2.6(m，2H)，2.3(m，1H)， 2.25(s，3H)，2.15(m，1H)，1.65(m，1H)。
Embodiment 112
N-[4-((R)-1-allyl group-pyrrolidin-3-yl)-phenyl]-4-(the fluoro-1-methyl-ethyl of 2,2,2-tri-)-benzsulfamide
ESI-MS：439.1[M+H] +
1H-NMR(CDCl 3，400MHz)： 7.8(d，2H)，7.4(d，2H)，7.15(d，2H)，7.0(d，2H)，5.9(m，1H)，5.2(d，1H)，5.1(d，1H)，3.45(m，1H)，3.3(m，1H)，3.2(m，2H)，3.1(m，1H)，2.9(m，1H)，2.7(m，1H)，2.5(m，1H)，2.3(m，1H)，1.8(m，1H)，1.5(d，3H)。
Embodiment 113
N-[4-((S)-1-allyl group-pyrrolidin-3-yl)-phenyl]-4-(the fluoro-1-methyl-ethyl of (R)-2-)-benzsulfamide
ESI-MS：403.1[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.75(d，2H)，7.3(d，2H)，7.15(d，2H)，7.0(d，2H)，5.9(m，1H)，5.2(d，1H)，5.1(d，1H)，4.5(m，1H)，4.4(m，1H)，3.3(m，1H)，3.1-3.2(m，3H)，3.0(m，1H)，2.8(m，1H)，2.65(m，1H)，2.4(m，1H)，2.25(m，1H)，1.8(m，1H)，1.3(d，3H)。
Embodiment 114
N-{4-[(S)-1-(the fluoro-propyl group of 3-)-pyrrolidin-3-yl]-phenyl }-4-trifluoromethoxy-benzsulfamide ESI-MS:447.1[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]10.25(bs，1H)，7.85(d，2H)，7.55(d，2H)，7.15(d，2H)，7.0(d，2H)，4.55(t，1H)，4.4(t，1H)，3.2(m，1H)，2.85(m，1H)，2.6(m，2H)，2.5(m，2H)，2.35(m，1H)，2.15(m，1H)，1.8(m，1H)，1.75(m，1H)，1.65(m，1H)。
Embodiment 115
4-methylsulfonyl-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
ESI-MS：423.1[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.95(m，4H)，7.1(d，2H)，7.0(d，2H)，6.2(bs，1H)，3.3(m，1H)，3.1(m，1H)，3.05(s，3H)，2.9(m，1H)，2.75(m，1H)，2.5(m，3H)，2.3(m，1H)，1.8(m，1H)，1.55(m，2H)， 0.9(t，3H)。
Embodiment 116
N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-4-urea groups-benzsulfamide
ESI-MS：403.1[M+H] +
Embodiment 117
4-cyano group-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
ESI-MS：370.1[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.85(d，2H)，7.7(d，2H)，7.1(d，2H)，6.95(d，2H)，6.0(bs，1H)，3.3(m，1H)，3.1(m，1H)，2.85(m，1H)，2.75(m，1H)，2.5(m，3H)，2.3(m，1H)，1.8(m，1H)，1.55(m，2H)，0.9(t，3H)。
Embodiment 118
4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
ESI-MS：425.1[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.75(s，1H)，7.7(d，2H)，7.65(s，1H)，7.45(d，2H)，7.1(d，2H)，7.0(d，2H)，3.9(s，3H)，3.3(m，1H)，3.05(m，1H)，2.85(m，1H)，2.7(m，1H)，2.5(m，3H)，2.3(m，1H)，1.8(m，1H)，1.55(m，2H)，0.9(t，3H)。
Embodiment 119
1-ethyl-1H-pyrazoles-4-sulfonic acid [4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-acid amides hydrochloric acid
ESI-MS：363.1[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.65(s，1H)，7.6(s，1H)，7.15(d，2H)，7.0(d，2H)，4，25(bs，1H)，4.1(q，2H)，3.3(m，1H)，3.0(m，1H)，2.8(m，1H)，2.65(m，1H)，2.4-2.55(m，3H)，2.3(m，1H)，1.8(m，1H)，1.55(m，2H)，1.4(t，3H)，0.9(t，3H)。
Embodiment 120
4-morpholine-4-base-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
0.07g rac-2,2 '-bis-(diphenylphosphino)-1,1 '-dinaphthalene (BINAP, 0.11mmol) and 0.043g tri-(dibenzalacetone) two palladiums (0) (0.05mmol) solution in 5ml tetrahydrofuran (THF) are added drop-wise to the bromo-N-[4-of 0.25g4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl] in-benzsulfamide (from embodiment 25 (0.59mmol)), 0.078ml morpholine (0.9mmol) and the solution of the tertiary Sodium propanecarboxylate of 0.104g (1.08mmol) in 20ml tetrahydrofuran (THF).By this reaction mixture refluxed 5.5 hours, and, after adding other 0.04ml morpholine, then reflux 2 hours.After evaporation, by resistates water treatment, use respectively ether and dichloromethane extraction, and by the organic layer dried over mgso merging, filter, and solvent is evaporated.By silica gel chromatography purifying, use methylene chloride/methanol 0-12% as gradient solvent the crude product so obtaining.
ESI-MS：430.2[M+H] +
1h-NMR (DMSO-d 6, 400MHz): δ [ppm] 11.25 (d is wide, 1H), and 10.05 (m, 1H), 9.4 (bs, 1H), 7.6 (d, 2H), 7.25 (d, 1H), 7.2 (d, 1H), 7.05 (m, 2H), 7.0 (d, 2H), 3.8 (m, 2H), 3.5-3.8 (m, 5H), 3.2 (m, 4H), 3.0-3.1 (m, 4H), 2.3 (m, 1H), 1.9 (m, 1H), 1.7 (m, 2H), 0.9 (t, 3H).
According to the method for above-described embodiment, made the compound of embodiment 121-132.Described compound characterizes by following physical data.
embodiment 121
4-benzyloxy-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
ESI-MS：451.1[M+H] +
embodiment 122
4-hydroxy-n-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
ESI-MS：361.1[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]10.0(bs，1H)，7.55(d，2H)，7.1(d，2H)，7.0(d，2H)，6.85(d，2H)，3.15(m，1H)，2.85(m，1H)，2.6(m，2H)，2.3-2.45(m，3H)，2.15(m，1H)，1.65(m，1H)，1.4(m，2H)，0.85(t，3H)。
embodiment 123
N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-4-vinyl-benzsulfamide
ESI-MS：371.1[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.7(d，2H)，7.4(d，2H)，7.15(d，2H)，7.0(d，2H)，6.7(q，1H)，5.8(d，1H)，5.4(d，1H)，4.25(bs，1H)，3.3(m，1H)，3.0(m，1H)，2.8(m，1H)，2.6(m，1H)，2.35-2.5(m，3H)，2.25(m，1H)，1.8(m，1H)，1.5(m，2H)，0.9(t，3H)。
embodiment 124
N-[2-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-4-vinyl-benzsulfamide
ESI-MS：371.1[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.75(d，2H)，7.4(d，2H)，7.05-7.2(m，3H)，6.95(d，1H)，6.65(q，1H)，5.8(d，1H)，5.35(d，1H)，5.0(bs)，3.45(m，1H)，3.3(m，1H)，3.15(m，1H)，3.1(m，1H)，2.65-2.8(m，3H)，2.3(m，1H)，1.9(m，1H)，1.7(m，2H)，0.9(t，3H)。
embodiment 125
The fluoro-N-[4-of 4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
ESI-MS：363.1[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]11.25(bd，1H)，10.4(m，1H)，7.8(m，2H)，7.4(m，2H)，7.3(d，1H)，7.25(d，1H)，7.1(m，2H)，3.2-3.8(m，5H)，2.9-3.1(m，2H)，2.3(m，1H)，1.95(m，1H)，1.7(m，2H)，0.9(t，3H)。
embodiment 126
The fluoro-N-[4-of 3,4-bis-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloric acid
ESI-MS：381.2[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]11.25(bd，1H)，10.55(m，1H)，7.85(t，1H)，7.65(m，2H)，7.3(d，1H)，7.25(d，1H)，7.1(m，2H)，3.2-3.8(m，5H)，2.9-3.15(m，2H)，2.3(m，1H)，1.95(m，1H)，1.7(m，2H)，0.9(t，3H)。
embodiment 127
4-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-N-[4-((S)-1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide
ESI-MS：450.1[M+H] +
embodiment 128
The fluoro-phenyl of N-[4-(1-benzyl-pyrrolidin-3-yl)-3-]-4-sec.-propyl-benzsulfamide
The fluoro-4-nitro-1-of 128.12-vinyl-benzene
1H-NMR(CDCl 3，400MHz)：δ[ppm]8.0(m，1H)，7.95(m，1H)，7.65(m，1H)，6.9(dd1H)，6.0(m，1H)，5.6(m，1H)。
128.21-benzyl-3-(the fluoro-4-nitro-phenyl of 2-)-tetramethyleneimine
ESI-MS：301.1[M+H] +
128.31-benzyl-3-(the fluoro-4-amino-phenyl of 2-)-tetramethyleneimine
ESI-MS：271.1[M+H] +
The fluoro-phenyl of 128.4N-[4-(1-benzyl-pyrrolidin-3-yl)-3-]-4-sec.-propyl-benzsulfamide
ESI-MS：453.15[M+H] +
According to the method for above-described embodiment, made the compound of embodiment 129-131.Described compound characterizes by following physical data.
embodiment 129
N-(the fluoro-4-pyrrolidin-3-yl-phenyl of 3-)-4-sec.-propyl-benzsulfamide
ESI-MS：363.15[M+H] +
embodiment 130
The fluoro-4-of N-[3-(1-propyl group-pyrrolidin-3-yl)-phenyl]-4-sec.-propyl-benzsulfamide hydrochloride
ESI-MS：405.15[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]11.2(bs，1H)，10.65(m，1H)，7.75(d，2H)，7.45(m，3H)，6.95(m，2H)，3.85-3.2(m，4H)，3.15-2.9(m，4H)，2.3(m，1H)，2.05(m，1H)，1.7(m，2H)，1.2(d，6H)，0.9(t，3H)。
embodiment 131
(-)-N-[6-(1-propyl group-pyrrolidin-3-yl)-pyridin-3-yl]-4-sec.-propyl-benzene-sulphonamide
By racemic compound N-[6-(1-propyl group-pyrrolidin-3-yl)-pyridin-3-yl]-4-sec.-propyl-benzene-sulphonamide carries out chiral chromatography separation on preparation CHIRACEL AD post, uses normal hexane/ethanol/triethylamine (85:15:1) as eluent.By analyzing chirality HPLC, analyze the level part that only contains required enantiomorph, and merge.
ESI-MS：388.1[M+H] +
[α] D：-18.1°
embodiment 132
(+)-N-[6-(1-propyl group-pyrrolidin-3-yl)-pyridin-3-yl]-4-sec.-propyl-benzene-sulfonamide hydrochloride
By racemic compound N-[6-(1-propyl group-pyrrolidin-3-yl)-pyridin-3-yl]-4-sec.-propyl-benzene-sulphonamide carries out chiral chromatography separation on preparation CHIRACEL AD post, uses normal hexane/ethanol/triethylamine (85:15:1) as eluent.By analyzing chirality HPLC, analyze the level part that only contains required enantiomorph, and merge.
ESI-MS：388.1[M+H] +
[α] D：+17.2°
embodiment 133
N-[4-((S)-1-propyl group-piperidines-3-yl)-phenyl]-4-trifluoromethoxy-benzsulfamide
133.1 (S)-3-phenyl-1-propyl group-piperidines
Commercially available (the S)-3-Phenylpiperidine of 1g (6.2mmol) is dissolved in methylene dichloride and 0.37ml acetic acid (6.51mmol).Add 0.5ml propionic aldehyde (6.93mmol) and 1.97g sodium triacetoxy borohydride (9.3mmol) afterwards, by this reaction mixture stirring at room 18 hours.Add water, separated each layer, and by water dichloromethane extraction.By the organic layer dried over mgso merging, filtration, and be evaporated to dryly, obtained 1.1g (S)-3-phenyl-1-propyl group-piperidines.
ESI-MS：204.1[M+H] +
133.2 (S)-3-(4-nitro-phenyl)-1-propyl group-piperidines
ESI-MS：249.1[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]8.15(d，2H)，7.4(d，2H)，2.95(m，4H)，2.3(m，2H)，1.9-2.1(m，3H)，1.65-1.85(m，2H)，1.4-1.6(m，2H)，0.9(t，3H)。
133.3 (S)-3-(4-amino-phenyl)-1-propyl group-piperidines
ESI-MS：219.1[M+H] +
133.4 N-[4-((S)-1-propyl group-piperidines-3-yl)-phenyl]-4-trifluoromethoxy-benzsulfamide
According to being similar to the method for describing in embodiment 55.2, realized sulphonamide coupling.
ESI-MS：443.1[M+H] +
1H-NMR(CDCl 3，400MHz)：δ[ppm]7.8(d，2H)，7.2(d，2H)，7.1(d，2H)，7.0(d，2H)，6.7(bs，1H)，3.0(m，2H)，2.8(m，1H)，2.35(m，2H)，1.95(m，2H)，1.85(m，1H)，1.75(m，2H)，1.5(m，2H)，1.4(m，1H)，0.9(t，3H)。
embodiment 134
The fluoro-4-of N-[2-(1-propyl group-pyrrolidin-3-yl)-phenyl] the fluoro-1-nitro-4-of-4-sec.-propyl-benzsulfamide hydrochloride 134.12-vinyl-benzene
By the fluoro-1-nitro-benzene of the bromo-2-of 4-(691mg, 3.14mmol), tributyl-vinyl-stannane (1.2g, 3.77mmol), triphenylphosphine (49mg, 0.19mmol) and tetra-triphenylphosphine palladium (0) (73mg, 0.06mmol) be dissolved in toluene (25ml), and stirring and refluxing 5 hours.By this reaction mixture vacuum concentration.Resistates is distributed between water (25ml) and ether (50ml).Isolate organic layer, by dried over mgso, filter and vacuum concentration, obtained oily matter (1.8g).Resistates, by silica gel chromatography purifying, is used to cyclohexane/ethyl acetate (gradient 0-5%) wash-out.The level that contains product part is merged, and by solvent evaporation, obtained oily matter (360mg, 69%).
134.2 1-benzyl-3-(the fluoro-4-nitro-phenyl of 3-)-tetramethyleneimine
By the fluoro-1-nitro-4-of 2-vinyl-benzene (360mg, 2.15mmol) be dissolved in methylene dichloride (2ml), add trifluoroacetic acid (70 μ l, 0.88mmol), then add lentamente N-benzyl-N-(methoxymethyl)-N-trimethyl silyl methylamine (633mg, 2.67mmol).In room temperature, continue to stir 2 hours.Add another part of N-benzyl-N-(methoxymethyl)-N-trimethyl silyl methylamine (300mg, 1.26mmol), and continue to stir 30 minutes.By this ethyl acetate (25ml) dilution for reaction mixture, with sodium bicarbonate aqueous solution (15ml) washing.By organic layer dried over mgso, filter, and the solvent was evaporated under reduced pressure, obtained oily matter (900mg).Crude product, via silica gel chromatography purifying, is used to cyclohexane/ethyl acetate (gradient 0-25%) wash-out.The level that contains product part is merged, by solvent evaporation, obtained oily matter (550mg, 85%).
ESI-MS：301.1[M+H] +
The fluoro-phenyl amine of 134.3 4-(1-benzyl-pyrrolidin-3-yl)-2-
1-benzyl-3-(the fluoro-4-nitro-phenyl of 3-)-tetramethyleneimine (550mg, 1.83mmol) is dissolved in methyl alcohol (30ml), adds tindichloride (3.125g, 16.48mmol), and by this reaction mixture stirring and refluxing 2 hours.By methyl alcohol evaporation, add 1N sodium hydroxide (60ml) and ethyl acetate, and continue to stir.Filter out pink salt, isolate organic layer, by dried over mgso, filter, and the solvent was evaporated under reduced pressure, obtained oily matter (400mg).
ESI-MS：271.1[M+H] +
The fluoro-phenyl of 134.4 N-[4-(1-benzyl-pyrrolidin-3-yl)-2-]-4-sec.-propyl-benzsulfamide
4-(1-benzyl-pyrrolidin-3-yl) the fluoro-phenyl amine of-2-(400mg, 1.48mmol) and 4-sec.-propyl-phenyl SULPHURYL CHLORIDE (324mg, 1.48mmol) are dissolved in tetrahydrofuran (THF) (25ml).Add triethylamine (0.62ml, 4.44mmol), and by this reaction mixture at stirred overnight at room temperature (10% transformation efficiency), 4 hours (30% transformation efficiency) then refluxes.4-sec.-propyl-phenyl the SULPHURYL CHLORIDE and the triethylamine that add aliquot stir this reaction mixture 15 minutes in 150 ℃ in microwave (CEM).Repeat this operation until observe conversion completely.The solvent was evaporated under reduced pressure, ethyl acetate for resistates (50ml) processed, by slightly slightly acidic water extracting twice.By organic layer dried over mgso, filter, and the solvent was evaporated under reduced pressure, obtained oily matter (170mg, 21%).
ESI-MS：453.1[M+H] +
134.5 N-(the fluoro-4-pyrrolidin-3-yl-phenyl of 2-)-4-sec.-propyl-benzsulfamide
By the fluoro-phenyl of N-[4-(1-benzyl-pyrrolidin-3-yl)-2-]-4-sec.-propyl-benzsulfamide (170mg, 0.31mmol) and the mixture hydrogenation of 10% palladium on carbon (20mg) in ethyl acetate (25ml) and acetic acid (10ml) spend the night (20% transformation efficiency).This reaction mixture is irradiated to 3 hours (transformation efficiency completely) with infrared lamp.Filter out catalyzer, and solvent removed in vacuo, oily matter (45mg, 64% purity, 26%) obtained.
ESI-MS：363.1[M+H] +
The fluoro-4-of 134.6 N-[2-(1-propyl group-pyrrolidin-3-yl)-phenyl]-4-sec.-propyl-benzsulfamide hydrochloride
N-(the fluoro-4-pyrrolidin-3-yl-phenyl of 2-)-4-sec.-propyl-benzsulfamide (45mg, 0.08mmol) and propionic aldehyde (4.7mg, 0.08mmol) are dissolved in tetrahydrofuran (THF) (5ml).Acetic acid (10 μ l, 0.12mmol) and sodium triacetoxy borohydride (34mg, 0.16mmol) are added in reaction mixture successively, and stirring at room 30 minutes.This reaction mixture is concentrated, and resistates is dissolved in sodium bicarbonate aqueous solution (10ml), and extract with ether (30ml).Isolate organic layer, by dried over mgso, filter, and be evaporated to dryly, obtained oily matter (45mg).Resistates is dissolved in ether (25ml), adds the diethyl ether solution of HCl, and stir and spend the night.Decant goes out solvent, and adds 3mlH in resistates 2o.By this solution lyophilize, obtained crude product (32mg, 91%).
ESI-MS：405.1[M+H] +
1H-NMR(CH 3OH-d 4)：δ[ppm]7.7(d，2H)，7.4(m，3H)，7.0(m，2H)，3.4(m，2H)，3.2-2.9(m，4H)，2.8(m，2H)，2.4(m，1H)，2.0(m，1H)，1.6(m，2H)，1.2(d，6H)，1.0(t，3H)。
embodiment 135
4-sec.-propyl-N-(2-methoxyl group-4-pyrrolidin-3-yl-phenyl)-benzsulfamide acetate
The bromo-2-methoxyl group-1-of 135.1 4-nitro-benzene
In solution to the 4-fluoro-1-nitro-benzene of bromo-2-(2.0g, 9.09mmol) in methyl alcohol (50ml), add sodium methylate (30% solution) in methyl alcohol (1.64g, 9.09mmol).By this reaction mixture in stirred overnight at room temperature.This reaction mixture is concentrated, and resistates is dissolved in water (30ml), be extracted with ethyl acetate twice.The organic phase of merging is washed with water.Isolate organic layer, by dried over mgso, filter, and be evaporated to dryly, obtained solid crystal (2.1g, 99%).
1H-NMR(DMSO-d 6)：δ[ppm]7.9(d，1H)，7.6(s，1H)，7.3(d，1H)，4.0(s，3H)。
135.2 2-methoxyl group-1-nitro-4-vinyl-benzene
By the bromo-2-methoxyl group-1-of 4-nitro-benzene (691mg, 3.14mmol), tributyl-vinyl-stannane (1.2g, 3.77mmol), triphenylphosphine (49mg, 0.19mmol) and tetra-triphenylphosphine palladium (0) (73mg, 0.06mmol) be dissolved in toluene (25ml), and stirring and refluxing 5 hours.By this reaction mixture vacuum concentration.Resistates is distributed between water (25ml) and ether (50ml).Isolate organic layer, by dried over mgso, filter and vacuum concentration, obtained oily matter (2.0g).Resistates, by silica gel chromatography purifying, is used to cyclohexane/ethyl acetate (gradient 0-25%) wash-out.The level that contains product part is merged, by solvent evaporation, obtained oily matter (435mg, 72%).
135.3 1-benzyl-3-(3-methoxyl group-4-nitro-phenyl)-tetramethyleneimine
By 2-methoxyl group-1-nitro-4-vinyl-benzene (435mg, 2.43mmol) be dissolved in methylene dichloride (2ml), add trifluoroacetic acid (80 μ l, 1.0mmol), then add lentamente N-benzyl-N-(methoxymethyl)-N-trimethyl silyl methylamine (715mg, 3.01mmol).In room temperature, continue to stir 2 hours.Add another part N-benzyl-N-(methoxymethyl)-N-trimethyl silyl methylamine (300mg, 1.26mmol), and continue to stir 30 minutes.By this ethyl acetate (25ml) dilution for reaction mixture, use NaHCO 3the aqueous solution (15ml) washing.By organic layer dried over mgso, filter, and the solvent was evaporated under reduced pressure, obtained oily matter (970mg).Crude product, via silica gel chromatography purifying, is used to cyclohexane/ethyl acetate (gradient 0-50%) wash-out.The level that contains product part is merged, by solvent evaporation, obtained oily matter (320mg, 46%).
ESI-MS：313.1[M+H] +
135.4 4-(1-benzyl-pyrrolidin-3-yl)-2-methoxyl group-phenyl amine
1-benzyl-3-(3-methoxyl group-4-nitro-phenyl)-tetramethyleneimine (350mg, 1.12mmol) is dissolved in methyl alcohol (20ml), adds tindichloride (1.912g, 10.08mmol), and by this reaction mixture stirring and refluxing 2 hours.By methyl alcohol evaporation, add 1N sodium hydroxide (50ml) and ethyl acetate and continue and stir.Filter out pink salt, isolate organic layer, by dried over mgso, filter, and the solvent was evaporated under reduced pressure, obtained oily matter (220mg, 70%).
ESI-MS：283.1[M+H] +
135.5 N-[4-(1-benzyl-pyrrolidin-3-yl)-2-methoxyl group-phenyl]-4-sec.-propyl-benzsulfamide
4-(1-benzyl-pyrrolidin-3-yl)-2-methoxyl group-phenyl amine (220mg, 0.78mmol) and 4-isopropyl phenyl SULPHURYL CHLORIDE (170mg, 0.78mmol) are dissolved in tetrahydrofuran (THF) (20ml).Add triethylamine (0.32ml, 2.34mmol), and by this reaction mixture at stirred overnight at room temperature (10% transformation efficiency), 4 hours (70% transformation efficiency) then refluxes.Add aliquot 4-isopropyl phenyl SULPHURYL CHLORIDE and a triethylamine, and this reaction mixture is stirred 15 minutes in 150 ℃ in microwave (CEM).The solvent was evaporated under reduced pressure, ethyl acetate for resistates (50ml) is processed, and by slightly slightly acidic water extracting twice.By organic layer dried over mgso, filter, and the solvent was evaporated under reduced pressure, obtained oily matter (470mg).Crude product, via silica gel chromatography purifying, is used to cyclohexane/ethyl acetate (gradient 0-100%) wash-out.The level that contains product part is merged, by solvent evaporation, obtained oily matter (143mg, 40%).
ESI-MS：465.1[M+H] +
135.64-sec.-propyl-N-(2-methoxyl group-4-pyrrolidin-3-yl-phenyl)-benzsulfamide acetate
By N-[4-(1-benzyl-pyrrolidin-3-yl)-2-methoxyl group-phenyl]-4-sec.-propyl-benzsulfamide (143mg, 0.31mmol) and the mixture of 10% palladium on carbon (20mg) in ethyl acetate (20ml) and acetic acid (20ml) be in room temperature hydrogenation 4 hours.Filter out catalyzer, and solvent removed in vacuo, oily matter (100mg, 71%) obtained.
ESI-MS：375.2[M+H] +
1H-NMR(D 2O)：δ[ppm]7.6(d，2H)，7.4(d，2H)，7.3(d，1H)，6.9(d，1H)，6.8(s，1H)，3.7(m，1H)，3.6-3.4(m，6H)，3.2(m，1H)，3.0(m，1H)，2.4(m，1H)，2.1(m，1H)，1.2(d，6H)。
embodiment 136
4-sec.-propyl-N-[2-methoxyl group-4-(1-propyl group-pyrrolidin-3-yl)-phenyl]-benzsulfamide hydrochloride
4-sec.-propyl-N-(2-methoxyl group-4-pyrrolidin-3-yl-phenyl)-benzsulfamide acetate (40mg, 0.09mmol) and propionic aldehyde (5.1mg, 0.09mmol) are dissolved in tetrahydrofuran (THF) (5ml).Acetic acid (10 μ l, 0.12mmol) and sodium triacetoxy borohydride (37mg, 0.18mmol) are added in reaction mixture successively, and stirring at room 30 minutes.This reaction mixture is concentrated, and resistates is dissolved in to NaHCO 3in the aqueous solution (10ml), and extract with ether (30ml).Isolate organic layer, by dried over mgso, filter, and be evaporated to dryly, obtained oily matter (30mg).Resistates is dissolved in ether (25ml), adds the diethyl ether solution of HCl, and stir and spend the night.Decant goes out solvent, and adds 3ml H in resistates 2o.By this solution lyophilize, obtained crude product (23mg, 48%).
ESI-MS：417.1[M+H] +
1H-NMR(CH 3OH-d 4)：δ[ppm]7.6(d，2H)，7.4(d，2H)，7.3(d，1H)，6.9(d，1H)，6.8(s，1H)，3.5(m，5H)，3.3-3.2(m，2H)，3.0-2.9(m，4H)，2.4(m，1H)，2.0(m，1H)，1.7(m，2H)，1.2(d，6H)，1.0(t，3H)。
embodiment 137
N-[4-(1-allyl group-pyrrolidin-3-yl)-2-methoxyl group-phenyl]-4-sec.-propyl-benzsulfamide hydrochloride
In 4-sec.-propyl-N-(2-methoxyl group-4-pyrrolidin-3-yl-phenyl) solution of-benzsulfamide acetate (40mg, 0.09mmol) in DMF (5ml), add allyl bromide 98 (8 μ l, 0.1mmol) and K 2cO 3(36mg, 0.26mmol).By this reaction mixture stirring at room 2 hours.By this reaction mixture water (35ml) dilution, with ether (20ml) extraction 2 times.Isolate organic layer, by dried over mgso, filter, and be evaporated to dryly, obtained oily matter (36mg).Resistates is dissolved in ether (25ml), adds the diethyl ether solution of HCl, and stir and spend the night.Decant goes out solvent, in resistates, adds 3ml H 2o.This solution lyophilize, obtained crude product (17mg, 37%).
ESI-MS：415.1[M+H] +
1H-NMR(CH 3OH-d 4)：δ[ppm]7.6(d，2H)，7.3(m，3H)，6.8(d，1H)，6.7(s，1H)，5.9(m，1H)，5.3(d，1H)，5.2(d，1H)，3.4(s，3H)，3.2(m，1H)，3.0-2.9(m，3H)，2.6(m，1H)，2.3(m，1H)，1.9(m，IH)，1.2(d，6H)。
embodiment 138
4-sec.-propyl-N-[4-(1-propyl group-piperidines-3-yl)-phenyl]-benzsulfamide hydrochloride
138.1 3-phenyl-1-propyl group-piperidines
3-phenyl-piperidines (4.0g, 24.81mmol) and propionic aldehyde (1.8ml, 24.81mmol) are dissolved in tetrahydrofuran (THF) (100ml).Acetic acid (2.14ml, 37.21mmol) and sodium triacetoxy borohydride (10.515g, 49.61mmol) are added in reaction mixture successively, and stirring at room 1 hour.This reaction mixture is concentrated, and resistates is dissolved in sodium bicarbonate aqueous solution (50ml) and ether (100ml).By organic phase dried over mgso, filter, and be evaporated to dryly, obtained crude product (4.6g, 87% purity).
ESI-MS：204.15[M+H] +
138.2 3-(4-nitro-phenyl)-1-propyl group-piperidines
To ice-cold 3-phenyl-1-propyl group-piperidines (4.6g, 19.73mmol) and KNO 3in (2.254g, 22.29mmol), add dense H 2sO 4.Allow this reaction mixture is warmed to room temperature, and stir other 30 minutes.To adding carefully ice in this reaction mixture, then pH regulator to 9-10, water is extracted with ethyl acetate several times.By organic phase dried over mgso, filter, and be evaporated to dryly, obtained crude product (5.2g, 81% purity).
ESI-MS：249.15[M+H] +
138.3 4-(1-propyl group-piperidines-3-yl)-phenyl amine
By 3-(4-nitro-phenyl)-1-propyl group-piperidines (5.2g, 1.86mmol) be dissolved in methyl alcohol (35ml), add tindichloride (3.78g, 16.74mmol), and this reaction mixture refluxed is stirred 2 hours, in stirred overnight at room temperature.By methyl alcohol evaporation, add 1N sodium hydroxide (50ml) and ethyl acetate, and continue to stir.Filter out pink salt, isolate organic layer, by dried over mgso, filter, and the solvent was evaporated under reduced pressure, obtained crude product (450mg, 90% purity).
138.4 4-sec.-propyl-N-[4-(1-propyl group-piperidines-3-yl)-phenyl]-benzsulfamide hydrochloride
4-(1-propyl group-piperidines-3-yl)-phenyl amine (600mg, 1.65mmol) and 4-sec.-propyl-phenyl SULPHURYL CHLORIDE (397mg, 1.81mmol) are dissolved in tetrahydrofuran (THF) (25ml).Add triethylamine (760 μ l, 5.44mmol), and by this reaction mixture stirring at room 72 hours.The solvent was evaporated under reduced pressure, ether for resistates (50ml) processed to water (3 * 30ml) extraction 3 times.By 1M HCl solution-treated for organic phase.With NaOH solution, this acidic solution is alkalized to pH9-10, then use ethyl acetate (25ml) extraction.By organic phase dried over mgso, filter, and the solvent was evaporated under reduced pressure, obtained crude product (580mg).Crude product, via silica gel chromatography purifying, is used to eluent ethyl acetate.The level that contains product part is merged, by solvent evaporation, obtained crude product, by adding the diethyl ether solution of 1N HCl to convert it into hydrochloride.Filter out precipitation and vacuum-drying, obtained crude product (283mg, 39%).
ESI-MS：401.15[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]10.3(s，1H)，10.25(bs，1H)，7.7(d，2H)，7.45(d，2H)，7.15(d，2H)，7.1(d，2H)，3.45(m，1H)，3.35(m，1H)，3.1-2.8(m，6H)，1.9(m，2H)，1.85(m，1H)，1.75(m，2H)，1.55(m，1H)，1.2(d，6H)，0.9(t，3H)。
According to the method that is similar to embodiment 138.4, made the compound of embodiment 139-142.Described compound characterizes by following physical data.
embodiment 139
N-[4-(1-propyl group-piperidines-3-yl)-phenyl]-4-trifluoromethoxy-benzsulfamide hydrochloride
ESI-MS：443.15[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]10.5(s，1H)，10.15(bs，1H)，7.9(d，2H)，7.6(d，2H)，7.2(d，2H)，7.1(d，2H)，3.45(m，2H)，3.1-2.8(m，5H)，1.9(m，2H)，1.85(m，1H)，1.7(m，2H)，1.55(m，1H)，0.9(t，3H)。
embodiment 140
4-difluoro-methoxy-N-[4-(1-propyl group-piperidines-3-yl)-phenyl]-benzsulfamide hydrochloride
ESI-MS：425.15[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]10.4(s，1H)，10.15(bs，1H)，7.85(d，2H)，7.4(t，J＝70Hz，1H)，7.35(d，2H)，7.15(d，2H)，7.1(d，2H)，3.45(m，1H)，3.4(m，1H)，3.1-2.8(m，5H)，1.9(m，2H)，1.85(m，1H)，1.75(m，2H)，1.55(m，1H)，0.9(t，3H)。
embodiment 141
N-[4-(1-propyl group-piperidines-3-yl)-phenyl]-4-(the fluoro-ethyl of 2,2,2-tri-)-benzsulfamide hydrochloride
ESI-MS：441.15[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]10.4(s，1H)，10.2(bs，1H)，7.8(d，2H)，7.55(d，2H)，7.15(d，2H)，7.1(d，2H)，3.8(q，2H)，3.45(m，1H)，3.4(m，1H)，3.1-2.8(m，5H)，1.9(m，2H)，1.85(m，1H)，1.7(m，2H)，1.55(m，1H)，0.9(t，3H)。
embodiment 142
4-(the fluoro-cyclopropyl of 2,2-bis-)-N-[4-(1-propyl group-piperidines-3-yl)-phenyl]-benzsulfamide hydrochloride
ESI-MS：435.15[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]10.35(s，1H)，10.15(bs，1H)，7.75(d，2H)，7.45(d，2H)，7.15(d，2H)，7.1(d，2H)，3.45(m，1H)，3.4(m，1H)，3.15-2.8(m，5H)，2.05(m，2H)，1.9(m，2H)，1.8(m，1H)，1.7(m，2H)，1.55(m，1H)，0.9(t，3H)。
embodiment 143
N-(3-piperidines-3-base-phenyl)-4-trifluoromethoxy-benzsulfamide
143.1 3-[3-(4-trifluoromethoxy-benzenesulfonyl is amino)-phenyl]-piperidines-1-formic acid tertiary butyl ester
3-(3-amino-phenyl)-piperidines-1-formic acid tertiary butyl ester (500mg, 1.81mmol) and dimethyl aminopyridine (30mg, 0.25mmol) are dissolved in tetrahydrofuran (THF) (40ml).Add 4-Trifluoromethoxyphen-l SULPHURYL CHLORIDE (519mg, 1.99mmol), and by this reaction mixture stirring at room 2 hours.Add again a certain amount of Trifluoromethoxyphen-l SULPHURYL CHLORIDE until the completely consumed of 3-(3-amino-phenyl)-piperidines-1-formic acid tertiary butyl ester has obtained two-sulfonylation product.The solvent was evaporated under reduced pressure, and resistates water (25ml) and ether (50ml) are processed.By organic phase dried over mgso, filter, and the solvent was evaporated under reduced pressure.Under inert atmosphere, resistates is dissolved in ethanol (30ml), add small pieces sodium Metal 99.5, and by this reaction stirring at room 1 hour.The solvent was evaporated under reduced pressure, and resistates water (25ml) and ether (50ml) are processed.By organic phase dried over mgso, filter, and the solvent was evaporated under reduced pressure, obtained crude product (385mg).Crude product, via silica gel chromatography purifying, is used to methylene chloride/methanol (gradient 100:0-97:3) wash-out.The level that contains product part is merged, by solvent evaporation, obtained crude product (340mg, 36%).
ESI-MS：445.05[M+H-C(CH 3) 3] +
143.2 N-(3-piperidines-3-base-phenyl)-4-trifluoromethoxy-benzsulfamide
By 3-[3-(4-trifluoromethoxy-benzenesulfonyl amino)-phenyl]-piperidines-1-formic acid tertiary butyl ester (340mg, 0.66mmol) is dissolved in methylene dichloride (30ml).Add trifluoroacetic acid (2ml), and by this reaction mixture stirring at room 1 hour.This reaction mixture is evaporated to dry.Add sodium bicarbonate aqueous solution (10ml), and by ethyl acetate (25ml) extracting twice.By the organic phase dried over mgso merging, filtration, and be evaporated to dryly, obtained crude product (250mg, 95% productive rate).
ESI-MS：401.05[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]7.85(d，2H)，7.5(d，2H)，7.1(t，1H)，6.9(d，1H)，6.85(m，2H)，2.95(m，2H)，2.5(m，3H)，1.75(m，1H)，1.65(m，1H)，1.45(m，2H)。
embodiment 144
4-sec.-propyl-N-(3-piperidines-3-base-phenyl)-benzsulfamide
144.1 3-[3-(4-sec.-propyl-benzenesulfonyl is amino)-phenyl]-piperidines-1-formic acid tertiary butyl ester
This title compound is to make according to being similar to the method for describing in embodiment 143.1.
ESI-MS：403.15[M+H-C(CH 3) 3] +
144.2 4-sec.-propyl-N-(3-piperidines-3-base-phenyl)-benzsulfamide
This title compound is to make according to being similar to the method for describing in embodiment 144.1.
ESI-MS：359.15[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]7.75(d，2H)，7.4(d，2H)，7.1(t，1H)，6.9(d，1H)，6.85(m，2H)，2.95(m，2H)，2.85(m，1H)，2.5-2.35(m，3H)，1.75(m，1H)，1.6(m，1H)，1.4(m，2H)，1.2(d，6H)。
embodiment 145
N-[3-(1-propyl group-piperidines-3-yl)-phenyl]-4-trifluoromethoxy-benzsulfamide hydrochloride
N-(3-piperidines-3-base-phenyl)-4-trifluoromethoxy-benzsulfamide (60mg, 0.15mmol) and propionic aldehyde (11 μ l, 0.15mmol) are dissolved in tetrahydrofuran (THF) (10ml).Acetic acid (14mg, 0.22mmol) and sodium triacetoxy borohydride (64mg, 0.30mmol) are added in reaction mixture successively, and stirring at room 1 hour.This reaction mixture is concentrated, and resistates is dissolved in sodium bicarbonate aqueous solution (5ml) and ether (25ml).By organic phase dried over mgso, filter, and be evaporated to dryly, obtained crude product (62mg).Crude product, via silica gel chromatography purifying, is used to methylene chloride/methanol (gradient 100:0-75:25) wash-out.The level that contains product part is merged, by solvent evaporation, obtained crude product (42mg), convert it into hydrochloride (45mg, 63%).
ESI-MS：443.15[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]10.45(s，1H)，10.25(bs，1H)，7.9(d，2H)，7.55(d，2H)，7.25(t，1H)，7.0(m，3H)，3.45(m，1H)，3.35(m，1H)，3.1-2.85(m，6H)，1.9(m，2H)，1.75(m，3H)，1.55(m，1H)，0.9(t，3H)。
embodiment 146
4-sec.-propyl-N-[3-(1-propyl group-piperidines-3-yl)-phenyl]-benzsulfamide hydrochloride
This title compound is to make according to being similar to the method for describing in embodiment 145.
ESI-MS：401.25[M+H] +
1H-NMR(DMSO-d 6，400MHz)：δ[ppm]10.3(s，1H)，10.15(bs，1H)，7.7(d，2H)，7.45(d，2H)，7.2(t，1H)，7.0(m，2H)，6.95(d，1H)，3.45(m，1H)，3.35(m，1H)，3.05-2.85(m，6H)，1.9(m，2H)，1.75(m，3H)，1.55(m，1H)，1.2(d，6H)，0.9(t，3H)。
iII. galenic form of medication embodiment
A) tablet
The tablet of following composition is suppressed on tabletting machine by ordinary method:
40mg derives from the material of embodiment 8
120mg W-Gum
13.5mg gel
45mg lactose
2.25mg (the chemical pure silicic acid of submicroscopic fine dispersion form)
6.75mg yam starch (being 6% paste)
B) sweet tablet tablet
20mg derives from the material of embodiment 8
60mg core starch
70mg saccharification composition
Core component comprises 9 parts of W-Gums, 3 parts of lactose and 1 part of 60:40 vinyl pyrrolidone/vinyl acetate copolymer.Saccharification composition is comprised of 5 portions of sucrose, 2 parts of W-Gums, 2 parts of calcium carbonate and 1 part of talcum powder.Anti-gastric juice dressing is provided then to the sweet tablet tablet of preparation in this way.
iV. biological test
Receptor binding assays:
Underproof substance dissolves methyl alcohol/ (BASF-AG) in or be dissolved in methyl-sulphoxide, then dilute with water is to obtain required concentration.
Dopamine D 3acceptor:
Analysis of mixtures (0.250ml) comprises and has stably express people dopamine D 3the deriving from of acceptor～10 6the film of individual HEK-293 cell, 0.1nM[ 125i]-iodosulpride and cultivate damping fluid (total binding) or, also have in addition substances (inhibition curve) or 1 μ M spiperone (non-specific binding).Each analysis of mixtures is to test in triplicate.
Cultivate damping fluid and contain 50mM tris, 120mM NaCl, 5mM KCl, 2mM CaCl 2, 2mM MgCl 2with 0.1% bovine serum albumin, 10 μ M quinolones and 0.1% xitix (same day is freshly prepd).Damping fluid is adjusted to pH7.4 with HCl.
Dopamine D 2Lacceptor:
Analysis of mixtures (1ml) comprises and has stably express people dopamine D 2Lthe deriving from of acceptor (long isotype)～10 6the film of individual HEK-293 cell and 0.01nM[ 125i] iodo spiperone and cultivate damping fluid (total binding) or, also have in addition substances (inhibition curve) or 1 μ M haloperidol (non-specific binding).Each analysis of mixtures is to test in triplicate.
Cultivate damping fluid and contain 50mM tris, 120mM NaCl, 5mM KCl, 2mM CaCl 2, 2mM MgCl 2with 0.1% bovine serum albumin.Damping fluid is adjusted to pH7.4 with HCl.Measure and analyze:
Be 25 ℃ cultivate 60 minutes after, under vacuum, with cell collection device, will identify that mixture filters by Whatman GF/B glass fibre filter.By strainer transfer system, strainer is transferred in scintillation vial.Add 4ml Ultima (Packard) afterwards, sample is shaken 1 hour, then use Beta-Counter (Packard, Tricarb2000 or 2200CA) to calculate radiant.By standard cancellation series (quench series) and the program that belongs to instrument, cpm is converted into dpm.
Use is similar to the statistical analysis system (SAS) of " LIGAND " program of Munson and Rodbard description, by iteration nonlinear regression analysis, analyzes inhibition curve.
As mentioned before, receptors bind research structure is expressed as to receptors bind constant K i(D 2) and K i(D 3), and provide in table 6.
In these trials, the compounds of this invention is to D 3acceptor shows extraordinary avidity (<50nM, or <10nM, conventionally <5nM), and optionally with D 3receptors bind.
In conjunction with test-results, provide in table 6.
Table 6:
Embodiment K i(D3) ＊[nM] K i(D2) ＊[nM] K i(D2) ＊/K i(D3) ＊
1 0.09 7.6 89
2 0.24 2.3 9
3 0.17 13.8 91
4 3.16 403 127
5 2.9 267 93
6 0.45 20.1 45
7 3.5 212 61
8 4.1 235 57
9 2.6 129 49
Embodiment K i(D3) ＊[nM] K i(D2) ＊[nM] K i(D2) ＊/K i(D3) ＊
10 1.9 111 60
12 3.0 131 43
13 3.1 168 54
14 3.4 123 37
15 1.9 74 39
16 12.6 393 31
17 3.1 126 41
18 2.3 90 39
19 0.48 12.6 26
20 0.3 7.3 24
21 0.4 11 27
23 1.07 46.6 44
24 1.2 72 60
25 1.6 95 60
26 28.1 1278 46
27 0.23 7.1 30
28 3.3 133 41
29 0.67 27.3 41
30 0.28 11.7 42
31 10.8 257 24
33 0.17 5.47 33
34 5.1 174 34
35 0.3 7.4 24
37 0.15 3.25 22
38 0.29 6.3 21
40 0.46 18.2 40
41 0.44 13.5 30
46 49 1.830 37
48 2.1 137 65
49 46 1,808 39
Embodiment K i(D3) ＊[nM] K i(D2) ＊[nM] K i(D2) ＊/K i(D3) ＊
53 0.41 5.85 14
54 0.32 8.73 27
55 7.11 1175 165
56 24.4 2661.2 109
57 7.18 880 123
58 39.80 2940.0 74
59 6.41 1525 238
60 7.63 7780 1019
61 21.3 -- --
62 25.2 3545 141
63 5.75 647.21 113
64 2.10 344 164
65 6.79 197 29
67 0.35 3.88 11
68 3.00 142 47
69 2.51 90.3 36
70 0.84 37.3 44
71 4.79 52.3 11
72 35.1 473 13
73 0.61 6.73 11
74 0.69 10.5 15
75 0.63 12.2 19
77 1.33 50 37
78 1.40 41.9 30
79 13.5 1111 82
80 37.6 1095 29
81 31.3 1162.0 37
82 5.59 437 78
84 0.95 16.2 17
85 0.57 18.5 32
Embodiment K i(D3) ＊[nM] K i(D2) ＊[nM] K i(D2) ＊/K i(D3) ＊
86 1.18 119 101
87 0.55 20.5 37
88 0.92 41 45
89 0.6 27 45
90 11 280 25
92 0.61 17.3 28
93 0.48 14.7 31
94 0.23 4.7 21
95 1.3 27.9 22
96 0.83 57.8 70
101 3.7 268 73
102 52 2714 52
103 1.2 45 38
104 8.3 352 43
105 6.1 309 51
107 0.42 45.8 108
108 11.2 203.8 18
109 7.4 257.9 35
110 6.6 895 135
111 16.4 723 44
112 10.3 1196 116
113 0.49 42.2 86
114 4.2 464 111
118 36.6 1169 32
120 2.0 174 86
121 3.7 163 44
122 43.9 1342 31
123 0.45 41 91
125 19.5 1305 67
126 34 1021 30
Embodiment K i(D3) ＊[nM] K i(D2) ＊[nM] K i(D2) ＊/K i(D3) ＊
127 0.6 64.7 112
128 2.7 12.9 5
129 3.6 106.3 30
130 0.52 8.5 16
131 5.8 430 74
133 7.3 192.7 26
134 0.76 13
135 0.85 17
136 0.27 6
137 0.36 12
*according to analyzing as mentioned above the receptors bind constant obtaining

Claims (22)

1. formula (I) compound and physiology thereof can tolerate acid salt
Wherein
N is 0,1 or 2;
G is CH 2or CHR 3;
R 1h, C 1-C 6-alkyl, by C 3-C 6the C of-cycloalkyl substituted 1-C 6-alkyl, C 1-C 6-hydroxyalkyl, fluoro C 1-C 6-alkyl, C 3-C 6-cycloalkyl, fluoro C 3-C 6-cycloalkyl, C 3-C 6-alkenyl, fluoro C 3-C 6-alkenyl, formyl radical, ethanoyl or propionyl;
R 2, R 3and R 4be H, methyl, methyl fluoride, difluoromethyl or trifluoromethyl independently of one another;
A is Isosorbide-5-Nitrae-phenylene, 1,2-phenylene, 2, and 5-pyridylidene, 3, the sub-pyrimidyl of 6-pyridylidene or 2,5-, described group can be selected from following substituting group and replace by one or more: halogen, methyl, methoxyl group and CF 3;
E is NR 5or CH 2, R wherein 5h or C 1-C 3-alkyl;
Ar is selected from following cyclic group: phenyl, and comprise 1,2 or 3 and be selected from the heteroatoms of N, O and S as 5 or 6 yuan of heteroaryls of ring members, and 1,2 or 3 substituent R of cyclic group Ar portability wherein a;
R ahalogen, C 1-C 6-alkyl, fluoro C 1-C 6-alkyl, C 1-C 6-hydroxyalkyl, C 1-C 6-alkoxy-C 1-C 6-alkyl, C 2-C 6-alkenyl, fluoro C 2-C 6-alkenyl, C 3-C 6-cycloalkyl, fluoro C 3-C 6-cycloalkyl, C 1-C 6-alkoxyl group, C 1-C 6-hydroxy alkoxy base, C 1-C 6-alkoxy-C 1-C 6-alkoxyl group, fluoro C 1-C 6-alkoxyl group, C 1-C 6-alkylthio, fluoro C 1-C 6-alkylthio, C 1-C 6-alkyl sulphinyl, fluoro C 1-C 6-alkyl sulphinyl, C 1-C 6-alkyl sulphonyl, fluoro C 1-C 6-alkyl sulphonyl, phenyl sulfonyl, benzyloxy, phenoxy group, wherein in the end the phenyl in 3 groups can be unsubstituted or portability 1-3 be selected from C 1-C 4-alkyl, fluoro C 1-C 4the substituting group of-alkyl and halogen, or R acN, nitro, C 1-C 6-alkyl-carbonyl, fluoro C 1-C 6-alkyl-carbonyl, C 1-C 6-alkyl-carbonyl-amino, fluoro C 1-C 6-alkyl-carbonyl-amino, carboxyl, NH-C (O)-NR 6r 7, NR 6r 7, NR 6r 7-C 1-C 6-alkylidene group, O-NR 6r 7, R wherein 6and R 7be H, C independently of one another 1-C 4-alkyl, fluoro C 1-C 4-alkyl or C 1-C 4-alkoxyl group, or can form 4,5 or 6 yuan of saturated or unsaturated rings together with N, or R abe saturated or unsaturated 3-7 unit heterocycle, wherein said heterocycle comprises 1,2,3 or 4 heteroatoms that is selected from N, O and S and/or 1,2 or 3 and is selected from NR 9, SO, SO 2with CO containing heteroatom group as ring members, R wherein 9h, C 1-C 4-alkyl, fluoro C 1-C 4-alkyl, C 1-C 4-alkyl-carbonyl or fluoro C 1-C 4-alkyl-carbonyl, and 1,2 or 3 of wherein said heterocycle portabilities are selected from hydroxyl, halogen, C 1-C 6-alkyl, fluoro C 1-C 6-alkyl and C 1-C 6the substituting group of-alkoxyl group.
2. the compound of claim 1
Wherein
R 1h, can be by C 3-C 6the C of-cycloalkyl substituted 1-C 6-alkyl, fluoro C 1-C 6-alkyl, C 3-C 6-cycloalkyl, fluoro C 3-C 6-cycloalkyl, C 3-C 6-alkenyl, fluoro C 3-C 6-alkenyl, formyl radical, ethanoyl or propionyl; And
Ar is selected from following cyclic group: phenyl, and comprise 1,2 or 3 and be selected from the heteroatoms of N, O and S as 5 or 6 yuan of heteroaryls of ring members, and wherein 1,2 or 3 of this cyclic group portabilities are selected from following substituent R a: halogen, C 1-C 6-alkyl, fluoro C 1-C 6-alkyl, C 3-C 6-cycloalkyl, fluoro C 3-C 6-cycloalkyl, C 1-C 6-alkoxyl group, fluoro C 1-C 6-alkoxyl group, CN, ethanoyl, carboxyl, NR 6r 7, NR 6r 7-C 1-C 6-alkylidene group and saturated or unsaturated 5 or 6 yuan of heterocycles, wherein said heterocycle comprises 1,2 or 3 heteroatoms that is selected from N, O and S as ring members, wherein R 6and R 7be H, C independently of one another 1-C 4-alkyl or fluoro C 1-C 4-alkyl, or can form 4,5 or 6 yuan of saturated or unsaturated rings together with N.
3. claim 1 or 2 compound, wherein n is 0 or 1.
4. the compound of claim 1, wherein R 1hydrogen, methyl, ethyl, n-propyl, 2-fluoro ethyl, 3-fluoropropyl, 3-hydroxypropyl, cyclopropyl methyl or allyl group.
5. the compound of claim 4, wherein R 1n-propyl or allyl group.
6. claim 1 or 2 compound, wherein R 2, R 3and R 4h.
7. claim 1 or 2 compound, wherein A is unsubstituted or is replaced by halogen.
8. claim 1 or 2 compound, wherein E is NH.
9. the compound of claim 1, wherein Ar is phenyl, thienyl, pyridyl, pyrimidyl, imidazolyl, isoxazolyl, thiazolyl, triazolyl or thiadiazolyl group, described group can be substituted as defined in claim 1.
10. the compound of claim 9, wherein Ar is phenyl, 2-or 3-thienyl, 2-, 3-or 4-pyridyl.
The compound of 11. claims 9, wherein Ar is phenyl, thienyl or pyridyl, described group can be substituted as defined in claim 2.
The compound of 12. claims 9, wherein Ar is phenyl, described phenyl carries 1,2 or 3 and is selected from following substituting group: halogen, C 1-C 6-alkyl, fluoro C 1-C 4-alkyl, C 1-C 4-alkoxyl group, fluoro C 1-C 4-alkoxyl group, C 2-C 4-alkenyl, fluoro C 2-C 4-alkenyl, CH 2n (CH 3) 2, NR 6r 7, the C that optionally replaced by halogen 3-C 6-cycloalkyl, ethanoyl or carboxyl, wherein R 6and R 7be H, C independently of one another 1-C 4-alkyl or fluoro C 1-C 4-alkyl, or Ar is thienyl or pyridyl, and described group is optionally by halogen, C 1-C 4-alkyl or C 1-C 4-alkenyl replaces.
The compound of 13. claims 1, wherein Ar carries a formula R a'shown in radicals R a
Wherein
Y is N, CH or CF,
If Y is CH or CF, R a1and R a2be independently from each other C 1-C 2-alkyl and fluoro C 1-C 2-alkyl, or a radicals R a1or R a2can also be hydrogen or fluorine, if or Y be CH, R a1and R a2in one be C 1-C 2-alkoxyl group, another is C 1-C 2-alkyl or hydrogen, or
If Y is CH or CF, R a1and R a2form together group (CH 2) m, wherein 1 or 2 hydrogen atom can be replaced by fluoro, and wherein m is 2,3,4 or 5, or R a1and R a2form together group (CH 2) m, wherein 1 or 2 hydrogen atom can be by fluorine, hydroxyl, C 1-C 2-alkyl or C 1-C 2-alkoxyl group replaces, one of them CH 2part is by O, S, SO, SO 2or NR creplace, wherein R ch or C 1-C 2-alkyl, and wherein m is 2,3,4,5 or 6; And
If Y is N, R a1and R a2be independently from each other C 1-C 2-alkyl, fluoro C 1-C 2-alkyl and C 1-C 2-alkoxyl group, or
R a1and R a2form together group (CH 2) m, wherein 1 or 2 hydrogen atom can be by fluorine, hydroxyl, C 1-C 2-alkyl or C 1-C 2-alkoxyl group replaces, one of them CH 2part can be by O, S, SO, SO 2or NR creplace, wherein R ch or C 1-C 2-alkyl, and wherein m is 2,3,4,5 or 6.
The compound of 14. claims 13, wherein radicals R a'be selected from sec.-propyl, (R)-1-fluoro ethyl, (S)-1-fluoro ethyl, 2-fluoro ethyl, 1, 1-bis-fluoro ethyls, 2, 2-bis-fluoro ethyls, 2, 2, 2-trifluoroethyl, (R)-1-fluoropropyl, (S)-1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1, 1-bis-fluoropropyls, 2, 2-bis-fluoropropyls, 3, 3-bis-fluoropropyls, 3, 3, 3-trifluoro propyl, (R) the fluoro-1-methylethyl of-2-, (S) the fluoro-1-methylethyl of-2-, (R)-2, the fluoro-1-methylethyl of 2-bis-, (S)-2, the fluoro-1-methylethyl of 2-bis-, (R)-1, the fluoro-1-methylethyl of 2-bis-, (S)-1, the fluoro-1-methylethyl of 2-bis-, (R)-2, 2, the fluoro-1-methylethyl of 2-tri-, (S)-2, 2, the fluoro-1-methylethyl of 2-tri-, the fluoro-1-of 2-(methyl fluoride) ethyl, 1-(difluoromethyl)-2, 2-bis-fluoro ethyls, cyclopropyl, cyclobutyl, 1-fluorine cyclopropyl, 2-fluorine cyclopropyl, (S)-2, 2-difluoro cyclopropyl and (R)-2, 2-difluoro cyclopropyl.
The compound of 15. claims 13, wherein radicals R a'carry 1,2,3 or 4 fluorine atom.
16. claims 1 or 2 compound, wherein Ar is phenyl, described phenyl carries radicals R in the 4-position of benzyl ring a.
17. claims 1 or 2 compound, wherein the absolute configuration on the carbon atom that carries group A is (S).
The compound of 18. claims 1, wherein Ar is phenyl, described phenyl is selected from following heterocyclic radical and is replaced: azetidinyl, pyrrolidyl, oxo-pyrrolidine base, Yang Dai oxazolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, 1-oxo thio-morpholinyl, 1, 1-dioxo thio-morpholinyl, pyrryl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl group and tetrazyl, wherein said heterocyclic radical can be unsubstituted or can carry 1-3 and be selected from following substituting group: halogen, C 1-C 4-alkyl, fluoro C 1-C 4-alkyl, C 1-C 4-alkoxyl group and hydroxyl.
The compound of 19. claims 18, wherein Ar is phenyl, described phenyl is selected from following heterocyclic radical and is replaced: azetidinyl, pyrrolidyl, oxo-pyrrolidine base, oxygen are for oxazolidinyl, morpholinyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl and thiadiazolyl group, and wherein said heterocyclic radical can be unsubstituted or can carry individual halogen and the C of being selected from of 1-3 1-C 4the substituting group of-alkyl.
20. pharmaceutical compositions, the compound that described pharmaceutical composition comprises at least one claim 1-19 any one, and optionally at least one pharmaceutically acceptable carrier or auxiliary substance.
The compound of 21. claim 1-19 any one for the preparation for the treatment of to using dopamine D 3application in the pharmaceutical composition of the illness of receptor ligands for treatment sensitivity.
The application of 22. claims 21, wherein said illness is central nervous system disease.
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